Bicyclic pyrimidines as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes

ABSTRACT

The present invention is directed to novel substituted bicyclic pyrimidines which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DPP-IV inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No.PCT/US2006/001660, filed 18 Jan. 2006, which claims the benefit under 35U.S.C. 119(e) of U.S. Provisional Application No. 60/645,220, filed 19Jan. 2005.

FIELD OF THE INVENTION

The present invention relates to novel substituted bicyclic pyrimidineswhich are inhibitors of the dipeptidyl peptidase-IV enzyme (“DPP-IVinhibitors”) and which are useful in the treatment or prevention ofdiseases in which the dipeptidyl peptidase-IV enzyme is involved, suchas diabetes and particularly Type 2 diabetes. The invention is alsodirected to pharmaceutical compositions comprising these compounds andthe use of these compounds and compositions in the prevention ortreatment of such diseases in which the dipeptidyl peptidase-IV enzymeis involved.

BACKGROUND OF THE INVENTION

Diabetes refers to a disease process derived from multiple causativefactors and characterized by elevated levels of plasma glucose orhyperglycemia in the fasting state or after administration of glucoseduring an oral glucose tolerance test. Persistent or uncontrolledhyperglycemia is associated with increased and premature morbidity andmortality. Often abnormal glucose homeostasis is associated bothdirectly and indirectly with alterations of the lipid, lipoprotein andapolipoprotein metabolism and other metabolic and hemodynamic disease.Therefore patients with Type 2 diabetes mellitus are at especiallyincreased risk of macrovascular and microvascular complications,including coronary heart disease, stroke, peripheral vascular disease,hypertension, nephropathy, neuropathy, and retinopathy. Therefore,therapeutical control of glucose homeostasis, lipid metabolism andhypertension are critically important in the clinical management andtreatment of diabetes mellitus.

There are two generally recognized forms of diabetes. In type 1diabetes, or insulin-dependent diabetes mellitus (IDDM), patientsproduce little or no insulin, the hormone which regulates glucoseutilization. In Type 2 diabetes, or noninsulin dependent diabetesmellitus (NIDDM), patients often have plasma insulin levels that are thesame or even elevated compared to nondiabetic subjects; however, thesepatients have developed a resistance to the insulin stimulating effecton glucose and lipid metabolism in the main insulin-sensitive tissues,which are muscle, liver and adipose tissues, and the plasma insulinlevels, while elevated, are insufficient to overcome the pronouncedinsulin resistance.

Insulin resistance is not primarily due to a diminished number ofinsulin receptors but to a post-insulin receptor binding defect that isnot yet understood. This resistance to insulin responsiveness results ininsufficient insulin activation of glucose uptake, oxidation and storagein muscle and inadequate insulin repression of lipolysis in adiposetissue and of glucose production and secretion in the liver.

The available treatments for Type 2 diabetes, which have not changedsubstantially in many years, have recognized limitations. While physicalexercise and reductions in dietary intake of calories will dramaticallyimprove the diabetic condition, compliance with this treatment is verypoor because of well-entrenched sedentary lifestyles and excess foodconsumption, especially of foods containing high amounts of saturatedfat. Increasing the plasma level of insulin by administration ofsulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, whichstimulate the pancreatic β-cells to secrete more insulin, and/or byinjection of insulin when sulfonylureas or meglitinide becomeineffective, can result in insulin concentrations high enough tostimulate the very insulin-resistant tissues. However, dangerously lowlevels of plasma glucose can result from administration of insulin orinsulin secretagogues (sulfonylureas or meglitinide), and an increasedlevel of insulin resistance due to the even higher plasma insulin levelscan occur. The biguanides increase insulin sensitivity resulting in somecorrection of hyperglycemia. However, the two biguanides, phenformin andmetformin, can induce lactic acidosis and nausea/diarrhea. Metformin hasfewer side effects than phenformin and is often prescribed for thetreatment of Type 2 diabetes.

The glitazones (i.e., 5-benzylthiazolidine-2,4-diones) are a morerecently described class of compounds with potential for amelioratingmany symptoms of Type 2 diabetes. These agents substantially increaseinsulin sensitivity in muscle, liver and adipose tissue in severalanimal models of Type 2 diabetes resulting in partial or completecorrection of the elevated plasma levels of glucose without occurrenceof hypoglycemia. The glitazones that are currently marketed are agonistsof the peroxisome proliferator activated receptor (PPAR), primarily thePPAR-gamma subtype. PPAR-gamma agonism is generally believed to beresponsible for the improved insulin sensitization that is observed withthe glitazones. Newer PPAR agonists that are being tested for treatmentof Type II diabetes are agonists of the alpha, gamma or delta subtype,or a combination of these, and in many cases are chemically differentfrom the glitazones (i.e., they are not thiazolidinediones). Seriousside effects (e.g. liver toxicity) have occurred with some of theglitazones, such as troglitazone.

Additional methods of treating the disease are still underinvestigation. New biochemical approaches that have been recentlyintroduced or are still under development include treatment withalpha-glucosidase inhibitors (e.g. acarbose) and protein tyrosinephosphatase-1B (PTP-1B) inhibitors.

Compounds that are inhibitors of the dipeptidyl peptidase-IV (“DPP-IV”)enzyme are under investigation as drugs that may be useful in thetreatment of diabetes, and particularly Type 2 diabetes. For adescription of various structural classes of DPP-IV inhibitors,reference is made to international patent publications WO 97/40832; WO98/19998; WO 01/68603; WO 02/38541; WO 02/076450; WO 03/000180; WO03/000181; WO 03/024942; WO 03/033524; WO 03/035057; WO 03/035067; WO03/037327; WO 03/074500; WO 03/082817; WO 04/007468; WO 04/018467; WO04/026822; WO 04/032836; WO 04/037181; WO 04/041795; WO 04/043940; WO04/046106; WO 04/050022; WO 04/058266; WO 04/064778; WO 04/069162; WO04/071454; U.S. Pat. Nos. 5,939,560; 6,011,155; 6,107,317; 6,110,949;6,166,063; 6,124,305; 6,303,661; 6,432,969; 6,617,340; and 6,699,871;Bioorg. Med. Chem. Lett., 6: 1163-1166 (1996); and Bioorg. Med. Chem.Lett., 6: 2745-2748 (1996). The usefulness of DPP-IV inhibitors in thetreatment of Type 2 diabetes is based on the fact that DPP-IV in vivoreadily inactivates glucagon like peptide-1 (GLP-1) and gastricinhibitory peptide (GIP). GLP-1 and GIP are incretins and are producedwhen food is consumed. The incretins stimulate production of insulin.Inhibition of DPP-IV leads to decreased inactivation of the incretins,and this in turn results in increased effectiveness of the incretins instimulating production of insulin by the pancreas. DPP-IV inhibitiontherefore results in an increased level of serum insulin.Advantageously, since the incretins are produced by the body only whenfood is consumed, DPP-IV inhibition is not expected to increase thelevel of insulin at inappropriate times, such as between meals, whichcan lead to excessively low blood sugar (hypoglycemia). Inhibition ofDPP-IV is therefore expected to increase insulin without increasing therisk of hypoglycemia, which is a dangerous side effect associated withthe use of insulin secretagogues.

DPP-IV inhibitors also have other therapeutic utilities, as discussedherein. DPP-IV inhibitors have not been studied extensively forutilities other than diabetes. New compounds are needed so that improvedDPP-IV inhibitors can be found for the treatment of diabetes andpotentially other diseases and conditions. The therapeutic potential ofDPP-IV inhibitors for the treatment of Type 2 diabetes is discussed byD. J. Drucker in Exp. Opin. Invest. Drugs, 12: 87-100 (2003); by K.Augustyns, et al., in Exp. Opin. Ther. Patents, 13: 499-510 (2003); andby C. F. Deacon, et al., in Exp. Opin. Investig. Drugs, 13: 1091-1102(2004).

SUMMARY OF THE INVENTION

The present invention is directed to novel substituted bicyclicpyrimidines which are inhibitors of the dipeptidyl peptidase-IV enzyme(“DPP-IV inhibitors”) and which are useful in the treatment orprevention of diseases in which the dipeptidyl peptidase-IV enzyme isinvolved, such as diabetes and particularly Type 2 diabetes. Theinvention is also directed to pharmaceutical compositions comprisingthese compounds and the use of these compounds and compositions in theprevention or treatment of such diseases in which the dipeptidylpeptidase-IV enzyme is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to substituted bicyclic pyrimidines thatare useful as inhibitors of dipeptidyl peptidase-IV. Compounds of thepresent invention are described by structural formula I:

and pharmaceutically acceptable salts thereof; whereineach n is independently 0, 1, 2, or 3;A is N or CR²;W¹ and W² are independently H or C₁₋₄ alkyl; or W¹ and W² together withthe carbon atom to which they are attached form a 3- to 6-memberedcarbocyclic ring;Z is phenyl or pyridyl, each of which is substituted with one to five R³substitutents;

-   R¹ and R² are each independently selected from the group consisting    of:    -   (1) hydrogen,    -   (2) C₁₋₁₀ alkyl, wherein alkyl is unsubstituted or substituted        with one to five substituents independently selected from:        -   (a) halogen,        -   (b) hydroxy,        -   (c) OR⁴,        -   (d) SR⁴,        -   (e) S(O)₁₋₂R⁴,        -   (f) SO₂NR⁵R⁶,        -   (g) NR⁵R⁶,        -   (h) NHSO₂R⁴,        -   (i) N(C₁₋₆ alkyl)SO₂R⁴,        -   (j) NHCONR⁵R⁶,        -   (k) N(C₁₋₆ alkyl)CONR⁵R⁶,        -   (l) NHCO₂R⁴,        -   (m) N(C₁₋₆ alkyl)CO₂R⁴,        -   (n) OCONR⁵R⁶,        -   (o) CN,        -   (p) CO₂H,        -   (q) CO₂C₁₋₆ alkyl,        -   (r) CONR⁵R⁶, and        -   (s) phenyl, which is unsubstituted or substituted with one            to five substituents independently selected from halogen,            CN, OH, R⁴, OR⁴, NHSO₂R⁴, N(C₁₋₆ alkyl)SO₂R⁴, SO₂R⁴,            SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CO₂H, and CO₂C₁₋₆ alkyl,    -   (3) phenyl, wherein phenyl is unsubstituted or substituted with        one to five substituents independently selected from halogen,        R⁴, OH, OR⁴, NHSO₂R⁴, N(C₁₋₆ alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶,        NR⁵R⁶, CONR⁵R⁶, CN, CO₂H, and CO₂C₁₋₆ alkyl,    -   (4) (CH₂)_(n)-heteroaryl, wherein heteroaryl is unsubstituted or        substituted with one to three substituents independently        selected from halogen, OH, R⁴, OR⁴, NHSO₂R⁴, N(C₁₋₆alkyl)SO₂R⁴,        SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CN, CO₂H, and CO₂C₁₋₆ alkyl,    -   (5) (CH₂)_(n)-heterocyclyl, wherein heterocyclyl is        unsubstituted or substituted with one to three substituents        independently selected from oxo, halogen, OH, R⁴, OR⁴, NHSO₂R⁴,        N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CN, CO₂H,        and CO₂C₁₋₆ alkyl,    -   (6) (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is        unsubstituted or substituted with one to five substituents        independently selected from halogen, OH, C₁₋₆ alkyl, and C₁₋₆        alkoxy, wherein alkyl and alkoxy are unsubstituted or        substituted with one to five halogens,    -   (7) hydroxy,    -   (8) OR⁴,    -   (9) SR⁴,    -   (10) S(O)₁₋₂R⁴,    -   (11) SO₂NR⁵R⁶,    -   (12) NR⁵R⁶,    -   (13) NHSO₂R⁴,    -   (14) N(C₁₋₆ alkyl)SO₂R⁴,    -   (15) NHCONR⁵R⁶,    -   (16) N(C₁₋₆ alkyl)CONR⁵R⁶,    -   (17) NHCO₂R⁴,    -   (18) N(C₁₋₆ alkyl)CO₂R⁴,    -   (19) OCONR⁵R⁶,    -   (20) CN,    -   (21) CO₂H,    -   (22) CO₂C₁₋₆ alkyl,    -   (23) CONR⁵R⁶, and    -   (24) halogen;        or wherein R¹ and R² together with the carbon atoms to which        they are attached form a 5- to 6-membered aromatic, heteroaryl,        carbocyclic, or heterocyclic ring; wherein said ring is        unsubstituted or substituted with one to five substituents        independently selected from halogen, hydroxy, C₁₋₆ alkyl, and        C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted or        substituted with one to five halogens;-   each R³ is independently selected from the group consisting of:    -   (1) halogen,    -   (2) C₁₋₆ alkyl, unsubstituted or substituted with one to five        substituents independently selected from halogen, hydroxy, and        C₁₋₄ alkoxy,    -   (3) C₁₋₆ alkoxy, unsubstituted or substituted with one to five        substituents independently selected from halogen, hydroxy, and        C₁₋₄ alkoxy,    -   (4) hydroxy,    -   (5) O(CH₂)_(n)-aryl, wherein aryl is unsubstituted or        substituted with one to five substituents independently selected        from halogen, methyl, hydroxy, and methoxy, and    -   (6) O(CH₂)_(n)-heteroaryl, wherein heteroaryl is unsubstituted        or substituted with one to five substituents independently        selected from halogen, methyl, hydroxy, and methoxy;-   R⁴ is C₁₋₆ alkyl, unsubstituted or substituted with one to five    substituents independently selected from halogen, hydroxy, methoxy,    CO₂H, and CO₂C₁₋₆ alkyl; and-   R⁵ and R⁶ are each independently selected from the group consisting    of:    -   (1) hydrogen,    -   (2) C₁₋₆ alkyl, unsubstituted or substituted with one to five        substituents independently selected from halogen, hydroxy, and        C₁₋₆ alkoxy,    -   (3) (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is        unsubstituted or substituted with one to five substituents        independently selected from halogen, OH, C₁₋₆ alkyl, and C₁₋₆        alkoxy, wherein alkyl and alkoxy are unsubstituted or        substituted with one to five halogens, and    -   (4) (CH₂)_(n)-phenyl, wherein phenyl is unsubstituted or        substituted with substituents independently selected from        halogen, OH, C₁₋₆ allyl, and C₁₋₆ alkoxy, wherein alkyl and        alkoxy are unsubstituted or substituted with one to five        halogens;        or wherein R⁵ and R⁶ together with the nitrogen atom to which        they are attached form a heterocyclic ring selected from        azetidine, pyrrolidine, piperidine, piperazine, and morpholine        wherein said heterocyclic ring is unsubstituted or substituted        with one to five substituents independently selected from        halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and        alkoxy are unsubstituted or substituted with one to five        halogens.

In one embodiment of the compounds of the present invention, A is N asdepicted in structural formula Ia:

In a class of this embodiment, W¹ and W² are H, and R¹ and Z are asdefined above.

In a subclass of this class, Z is phenyl which is substituted with twoto five R³ substituents;

-   each n is independently 0, 1, 2, or 3;-   R¹ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) C₁₋₄ alkyl, wherein alkyl is unsubstituted or substituted        with one to five substituents independently selected from:        -   (a) halogen,        -   (b) hydroxy,        -   (c) OR⁴,        -   (d) SR⁴, and        -   (e) NR⁵R⁶,    -   (3) (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is        unsubstituted or substituted with one to five substituents        independently selected from halogen, OH, C₁₋₆ alkyl, and C₁₋₆        alkoxy,    -   (4) hydroxy,    -   (5) OR⁴,    -   (6) SR⁴, and    -   (7) NR⁵R⁶;-   each R³ is independently selected from the group consisting of:    -   (1) halogen,    -   (2) C₁₋₄ alkyl, unsubstituted or substituted with one to five        substituents independently selected from halogen, hydroxy, and        C₁₋₄ alkoxy,    -   (3) C₁₋₄ alkoxy, unsubstituted or substituted with one to five        substituents independently selected from halogen, hydroxy, and        C₁₋₄ alkoxy,    -   (4) hydroxy,    -   (5) O(CH₂)_(n)-aryl, wherein aryl is unsubstituted or        substituted with one to five substituents independently selected        from halogen, methyl, hydroxy, and methoxy, and    -   (6) O(CH₂)_(n)-heteroaryl, wherein heteroaryl is unsubstituted        or substituted with one to five substituents independently        selected from halogen, methyl, hydroxy, and methoxy;-   R⁴ is C₁₋₆ alkyl, unsubstituted or substituted with one to five    substituents independently selected from halogen, hydroxy, and    methoxy; and-   R⁵ and R⁶ are each independently selected from the group consisting    of:    -   (1) hydrogen,    -   (2) C₁₋₄ alkyl, unsubstituted or substituted with one to five        substituents independently selected from halogen, hydroxy, and        C₁₋₄ alkoxy, and    -   (3) (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is        unsubstituted or substituted with one to five substituents        independently selected from halogen, OH, C₁₋₄ alkyl, and C₁₋₄        alkoxy, wherein alkyl and alkoxy are unsubstituted or        substituted with one to five halogens;    -   or wherein R⁵ and R⁶ together with the nitrogen atom to which        they are attached form a heterocyclic ring selected from        azetidine, pyrrolidine, piperidine, piperazine, and morpholine.

In a second embodiment of the compounds of the present invention, A isCR² as depicted in structural formula Ib:

In a class of this embodiment, W¹ and W² are H, and R¹, R², and Z are asdefined above.

In a subclass of this class, Z is phenyl which is substituted with twoto five R³ substituents;

-   each n is independently 0, 1, 2, or 3;-   R¹ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) C₁₋₄ alkyl, wherein alkyl is unsubstituted or substituted        with one to five substituents independently selected from:        -   (a) halogen,        -   (b) hydroxy,        -   (c) OR⁴,        -   (d) SR⁴, and        -   (e) NR⁵R⁶,    -   (3) (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is        unsubstituted or substituted with one to five substituents        independently selected from halogen, OH, C₁₋₆ alkyl, and C₁₋₆        alkoxy,    -   (4) hydroxy,    -   (5) OR⁴,    -   (6) SR⁴, and    -   (7) NR⁵R⁶;-   R² is selected from the group consisting of:    -   (1) hydrogen,    -   (2) C₁₀ alkyl, wherein alkyl is unsubstituted or substituted        with one to five substituents independently selected from:        -   (a) halogen,        -   (b) hydroxy,        -   (c) OR⁴,        -   (d) SR⁴,        -   (e) S(O)₁₋₂R⁴,        -   (f) SO₂NR⁵R⁶,        -   (g) NR⁵R⁶,        -   (h) NHSO₂R⁴,        -   (i) N(C₁₋₆alkyl)SO₂R⁴,        -   (j) NHCONR⁵R⁶,        -   (k) N(C₁₋₆ alkyl)CONR⁵R⁶,        -   (l) NHCO₂R⁴,        -   (m) N(C₁₋₆ alkyl)CO₂R⁴,        -   (n) OCONR⁵R⁶,        -   (o) CN,        -   (p) CO₂H,        -   (q) CO₂C₁₋₆ alkyl,        -   (r) CONR⁵R⁶, and        -   (s) phenyl, which is unsubstituted or substituted with one            to five substituents independently selected from halogen,            CN, OH, R⁴, OR⁴, NHSO₂R⁴, N(C₁₋₆ alkyl)SO₂R⁴, SO₂R⁴,            SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CO₂H, and CO₂C₁₋₆ alkyl,    -   (3) phenyl which is unsubstituted or substituted with one to        five substituents independently selected from halogen, R⁴, OH,        OR⁴, NHSO₂R⁴, N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶,        CONR⁵R⁶, CN, CO₂H, and CO₂C₁₋₆ alkyl,    -   (4) (CH₂)_(n)-heteroaryl, wherein heteroaryl is unsubstituted or        substituted with one to three substituents independently        selected from halogen, OH, R⁴, OR⁴, NHSO₂R⁴, N(C₁₋₆alkyl)SO₂R⁴,        SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CN, CO₂H, and CO₂C₁₋₆ alkyl,    -   (5) (CH₂)_(n)-heterocyclyl, wherein heterocyclyl is        unsubstituted or substituted with one to three substituents        independently selected from oxo, halogen, OH, R⁴, OR⁴, NHSO₂R⁴,        N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CN, CO₂H,        and CO₂C₁₋₆ alkyl,    -   (6) (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is        unsubstituted or substituted with one to five substituents        independently selected from halogen, OH, C₁₋₆ alkyl, and C₁₋₆        alkoxy, wherein alkyl and alkoxy are unsubstituted or        substituted with one to five halogens,    -   (7) hydroxy,    -   (8) OR⁴,    -   (9) SR⁴,    -   (10) S(O)₁₋₂R⁴,    -   (11) SO₂NR⁵R⁶,    -   (12) NR⁵R⁶,    -   (13) NHSO₂R⁴,    -   (14) N(C₁₋₆alkyl)SO₂R⁴,    -   (15) NHCONR⁵R⁶,    -   (16) N(C₁₋₆ alkyl)CONR⁵R⁶,    -   (17) NHCO₂R⁴,    -   (18) N(C₁₋₆ alkyl)CO₂R⁴,    -   (19) OCONR⁵R⁶,    -   (20) CN,    -   (21) CO₂H,    -   (22) CO₂C₁₋₆ alkyl,    -   (23) CONR⁵R⁶, and    -   (24) halogen,-   or wherein R¹ and R² together with the carbon atoms to which they    are attached form a 5-6 membered aromatic, heteroaryl, carbocyclic,    or heterocyclic ring;-   each R³ is independently selected from the group consisting of:    -   (1) halogen,    -   (2) C₁₋₄ alkyl, unsubstituted or substituted with one to five        substituents independently selected from halogen, hydroxy, and        C₁₋₄ alkoxy,    -   (3) C₁₋₄ alkoxy, unsubstituted or substituted with one to five        substituents independently selected from halogen, hydroxy, and        C₁₋₄ alkoxy,    -   (4) hydroxy,    -   (5) O(CH₂)_(n)-aryl, wherein aryl is unsubstituted or        substituted with one to five substituents independently selected        from halogen, methyl, hydroxy, and methoxy, and    -   (6) O(CH₂)_(n)-heteroaryl, wherein heteroaryl is unsubstituted        or substituted with one to five substituents independently        selected from halogen, methyl, hydroxy, and methoxy;-   R⁴ is C₁₋₆ alkyl, unsubstituted or substituted with one to five    substituents independently selected from halogen, hydroxy, and    methoxy; and-   R⁵ and R⁶ are independently selected from the group consisting of:    -   (1) hydrogen,    -   (2) C₁₋₄ alkyl, unsubstituted or substituted with one to five        substituents independently selected from halogen, hydroxy, and        C₁₋₄ alkoxy, and    -   (3) (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is        unsubstituted or substituted with one to five substituents        independently selected from halogen, OH, C₁₋₄ alkyl, and C₁₋₄        alkoxy, wherein alkyl and alkoxy are unsubstituted or        substituted with one to five halogens;    -   or wherein R⁵ and R⁶ together with the nitrogen atom to which        they are attached form a heterocyclic ring selected from        azetidine, pyrrolidine, piperidine, piperazine, and morpholine.

In a further embodiment of the compounds in the present invention, W¹and W² are H as depicted in structural formula Ic:

-   wherein each n is independently 0, 1, 2, or 3;-   A is N or CR²;-   R³ is chloro or methyl, which is unsubstituted or substituted with    one to three fluorine atoms;-   R⁷ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆ alkyl, unsubstituted or substituted with one to five        substituents independently selected from halogen, hydroxy, and        C₁₋₄ alkoxy,    -   (4) C₁₋₆ alkoxy, unsubstituted or substituted with one to five        substituents independently selected from halogen, hydroxy, and        C₁₋₄ alkoxy,    -   (5) hydroxy,    -   (6) O(CH₂)_(n)-aryl, wherein aryl is unsubstituted or        substituted with one to five substituents independently selected        from halogen, methyl, hydroxyl, and methoxy, and    -   (7) O(CH₂)_(n)-heteroaryl, wherein heteroaryl is unsubstituted        or substituted with one to five substituents independently        selected from halogen, methyl, hydroxyl, and methoxy;-   R¹ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) C₁₋₄ alkyl, wherein alkyl is unsubstituted or substituted        with one to five substituents independently selected from:        -   (a) halogen,        -   (b) hydroxy,        -   (c) OR⁴,        -   (d) SR⁴, and        -   (e) NR⁵R⁶,    -   (3) (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is        unsubstituted or substituted with one to five substituents        independently selected from halogen, OH, C₁₋₆ alkyl, and C₁₋₆        alkoxy,    -   (4) hydroxy,    -   (5) OR⁴,    -   (6) SR⁴, and    -   (7) NR⁵R⁶; and-   R² is selected from the group consisting of:    -   (1) hydrogen,    -   (2) C₁₋₁₀ alkyl, wherein alkyl is unsubstituted or substituted        with one to five substituents independently selected from:        -   (a) halogen,        -   (b) hydroxy,        -   (c) OR⁴,        -   (d) SR⁴,        -   (e) S(O)₁₋₂R⁴,        -   (f) SO₂NR⁵R⁶,        -   (g) NR⁵R⁶,        -   (h) NHSO₂R⁴,        -   (i) N(C₁₋₆alkyl)SO₂R⁴,        -   (j) NHCONR⁵R⁶,        -   (k) N(C₁₋₆ alkyl)CONR⁵R⁶,        -   (l) NHCO₂R⁴,        -   (m) N(C₁₋₆ alkyl)CO₂R⁴,        -   (n) OCONR⁵R⁶,        -   (o) CN,        -   (p) CO₂H,        -   (q) CO₂C₁₋₆ alkyl,        -   (r) CONR⁵R⁶, and        -   (s) phenyl, which is unsubstituted or substituted with one            to five substituents independently selected from halogen,            CN, OH, R⁴, OR⁴, NHSO₂R⁴, N(C₁₋₆ alkyl)SO₂R⁴, SO₂R⁴,            SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CO₂H, and CO₂C₁₋₆ alkyl,    -   (3) phenyl which is unsubstituted or substituted with one to        five substituents independently selected from halogen, R⁴, OH,        OR⁴, NHSO₂R⁴, N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶,        CONR⁵R⁶, CN, CO₂H, and CO₂C₁₋₆ alkyl,    -   (4) (CH₂)_(n)-heteroaryl, wherein heteroaryl is unsubstituted or        substituted with one to three substituents independently        selected from halogen, OH, R⁴, OR⁴, NHSO₂R⁴, N(C₁₋₆alkyl)SO₂R⁴,        SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CN, CO₂H, and CO₂C₁₋₆ alkyl,    -   (5) (CH₂)_(n)-heterocyclyl, wherein heterocyclyl is        unsubstituted or substituted with one to three substituents        independently selected from oxo, halogen, OH, R⁴, OR⁴, NHSO₂R⁴,        N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CN, CO₂H,        and CO₂C₁₋₆ alkyl,    -   (6) (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is        unsubstituted or substituted with one to five substituents        independently selected from halogen, OH, C₁₋₆ alkyl, and C₁₋₆        alkoxy, wherein alkyl and alkoxy are unsubstituted or        substituted with one to five halogens,    -   (7) hydroxy,    -   (8) OR⁴,    -   (9) SR⁴,    -   (10) S(O)₁₋₂R⁴,    -   (11) SO₂NR⁵R⁶,    -   (12) NR⁵R⁶,    -   (13) NHSO₂R⁴,    -   (14) N(C₁₋₆alkyl)SO₂R⁴,    -   (15) NHCONR⁵R⁶,    -   (16) N(C₁₋₆ alkyl)CONR⁵R⁶,    -   (17) NHCO₂R⁴,    -   (18) N(C₁₋₆ alkyl)CO₂R⁴,    -   (19) OCONR⁵R⁶,    -   (20) CN,    -   (21) CO₂H,    -   (22) CO₂C₁₋₆ alkyl,    -   (23) CONR⁵R⁶, and    -   (24) halogen;    -   or wherein R¹ and R² together with the carbon atoms to which        they are attached form a five to six-membered aromatic,        heteroaryl, carbocyclic, or heterocyclic ring.

Illustrative, but nonlimiting, examples of compounds of the presentinvention that are useful as DPP-IV inhibitors are the followingstructures and pharmaceutically acceptable salts thereof:

6-(aminomethyl)-5-mesityl-3-methylpyrazolo[1,5-a]pyrimidin-7-amine

6-(aminomethyl)-5-mesityl-3-methoxypyrazolo[1,5-a]pyrimidin-7-amine

6-(aminomethyl)-5-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

6-(aminomethyl)-2-cyclopropyl-5-mesityl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

6-(aminomethyl)-5-mesityl[1,2,4]triazolo[1,5-a]pyrimidine-2,7-diamine

6-(aminomethyl)-5-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine-2,7-diamine

6-(aminomethyl)-5-(2,4,6-trichlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine-2,7-diamine

6-(aminomethyl)-5-mesityl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

6-(aminomethyl)-5-(2,4,6-trichlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

6-(aminomethyl)-5-(2,4-dimethylphenyl)-3-methylpyrazolo[1,5-a]pyrimidin-7-amine

6-(aminomethyl)-3-methyl-5-(2,4,6-trichlorophenyl)pyrazolo[1,5-a]pyrimidin-7-amine

6-(aminomethyl)-5-mesityl-2,3-dimethylpyrazolo[1,5-a]pyrimidin-7-amine

6-(aminomethyl)-5-(2,4,6-trichlorophenyl)pyrazolo[1,5-a]pyrimidin-7-amine

[7-amino-6-(aminomethyl)-5-mesityl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]methanol

6-(aminomethyl)-5-mesityl-2-(methylthio)pyrazolo[1,5-a]pyrimidin-7-amine

As used herein the following definitions are applicable.

“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxyand alkanoyl, means carbon chains which may be linear or branched, andcombinations thereof, unless the carbon chain is defined otherwise.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and thelike.

The term “cycloalkyl” refers to a saturated hydrocarbon containing onering having a specified number of carbon atoms. Examples of cycloalkylinclude cyclopropyl (cPr), cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, and the like. A cycloalkyl group is monocyclicunless stated otherwise. Cycloalkyl groups are saturated unlessotherwise defined.

The term “alkoxy” refers to straight or branched chain alkoxides of thenumber of carbon atoms specified (e.g., C₁₋₁₀ alkoxy), or any numberwithin this range [i.e., methoxy (MeO—), ethoxy, isopropoxy, etc.].

The term “alkylthio” refers to straight or branched chain allylsulfidesof the number of carbon atoms specified (e.g., C₁₋₆alkylthio), or anynumber within this range [i.e., methylthio (MeS—), ethylthio,isopropylthio, etc.].

The term “alkylamino” refers to straight or branched alkylamines of thenumber of carbon atoms specified (e.g., C₁₋₆ alkylamino), or any numberwithin this range [i.e., methylamino, ethylamino, isopropylamino,t-butylamino, etc.].

The term “alkylsulfonyl” refers to straight or branched chainalkylsulfones of the number of carbon atoms specified (e.g., C₁₋₆alkylsulfonyl), or any number within this range [i.e., methylsulfonyl(MeSO₂—), ethylsulfonyl, isopropylsulfonyl, etc.].

The term “alkyloxycarbonyl” refers to straight or branched chain estersof a carboxylic acid derivative of the present invention of the numberof carbon atoms specified (e.g., C₁₋₆ alkyloxycarbonyl), or any numberwithin this range [i.e., methyloxycarbonyl (MeOCO—), ethyloxycarbonyl,or butyloxycarbonyl].

“Aryl” means a mono- or polycyclic aromatic ring system containingcarbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.The most preferred aryl is phenyl.

The term “heterocyclyl” refers to saturated or unsaturated non-aromaticrings or ring systems containing at least one heteroatom selected fromO, S and N, further including the oxidized forms of sulfur, namely SOand SO₂. Examples of heterocycles include tetrahydrofuran (THF),dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine,piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline,pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane,1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, pyrrolidinone,oxazolidin-2-one, imidazolidine-2-one, pyridone, and the like.

“Heteroaryl” means an aromatic or partially aromatic heterocycle thatcontains at least one ring heteroatom selected from O, S and N.Heteroaryls also include heteroaryls fused to other kinds of rings, suchas aryls, cycloalkyls and heterocycles that are not aromatic. Examplesof heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl,pyrazolyl, pyridinyl, 2-oxo-(1H)-pyridinyl (2-hydroxypyridinyl),oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl,pyrimidinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl,indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl,phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl,quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl,benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl,dibenzofuranyl, imidazo[1,2-a]pyridinyl,[1,2,4-triazolo][4,3-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,[1,2,4-triazolo][1,5-a]pyridinyl, 2-oxo-1,3-benzoxazolyl,4-oxo-3H-quinazolinyl, 3-oxo-[1,2,4]-triazolo[4,3-a]-2H-pyridinyl,5-oxo-[1,2,4]-4H-oxadiazolyl, 2-oxo-[1,3,4]-3H-oxadiazolyl,2-oxo-1,3-dihydro-2H-imidazolyl, 3-oxo-2,4-dihydro-3H-1,2,4-triazolyl,imidazo[1,2-a]pyrimidinyl, imidazo[1,5-a]pyrimidinyl,pyrazolo[1,5-a]pyrimidinyl, [1,2,4-triazolo][1,5-a]pyrimidinyl,[1,2,4-triazolo][4,3-a]pyrimidinyl, [1,2,3-triazolo][1,5-a]pyrimidinyl,pyrazolo[1,5-b]pyridazinyl, imidazo[1,5-b]pyridazinyl,imidazo[1,2-b]pyridazinyl, [1,2,4-triazolo][4,3-b]pyridazinyl,[1,2,4-triazolo][1,5-b]pyridazinyl, pyrido[2,3-b]pyrazinyl,pyrido[3,2-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, and the like. Forheterocyclyl and heteroaryl groups, rings and ring systems containingfrom 3-15 atoms are included, forming 1-3 rings.

“Halogen” refers to fluorine, chlorine, bromine and iodine. Chlorine andfluorine are generally preferred. Fluorine is most preferred when thehalogens are substituted on an alkyl or alkoxy group (e.g. CF₃₀ andCF₃CH₂O).

The compounds of the present invention contain one or more asymmetriccenters and can thus occur as racemates, racemic mixtures, singleenantiomers, diastereomeric mixtures, and individual diastereomers.Additional asymmetric centers may be present depending upon the natureof the various substituents on the molecule. Each such asymmetric centerwill independently produce two optical isomers and it is intended thatall of the possible optical isomers and diastereomers in mixtures and aspure or partially purified compounds are included within the ambit ofthis invention. The present invention is meant to comprehend all suchisomeric forms of these compounds.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist as tautomers, whichhave different points of attachment of hydrogen accompanied by one ormore double bond shifts. For example, a ketone and its enol form areketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed with compounds of the present invention.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the X-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

It will be understood that, as used herein, references to the compoundsof structural formula I are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds ortheir pharmaceutically acceptable salts or in other syntheticmanipulations.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic or organic basesand inorganic or organic acids. Salts of basic compounds encompassedwithin the term “pharmaceutically acceptable salt” refer to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present inventioninclude, but are not limited to, the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, camsylate, carbonate, chloride, clavulanate, citrate, edetate,edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, hexylresorcinate, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammoniumsalt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate,subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodide and valerate. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof include, but are not limited to, salts derived frominorganic bases including aluminum, ammonium, calcium, copper, ferric,ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium,zinc, and the like. Particularly preferred are the ammonium, calcium,magnesium, potassium, and sodium salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, cyclic amines, and basicion-exchange resins, such as arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,isopropylamine, lysine, methylglucamine, morpholine, piperazine,piperidine, polyamine resins, procaine, purines, theobromine,triethylamine, trimethylamine, tripropylamine, tromethamine, and thelike.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds of the present invention, pharmaceuticallyacceptable esters of carboxylic acid derivatives, such as methyl, ethyl,or pivaloyloxymethyl, or acyl derivatives of alcohols, such as acetateor maleate, can be employed. Included are those esters and acyl groupsknown in the art for modifying the solubility or hydrolysischaracteristics for use as sustained-release or prodrug formulations.

Solvates, and in particular, the hydrates of the compounds of structuralformula I are included in the present invention as well.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein.

The subject compounds are useful in a method of inhibiting thedipeptidyl peptidase-IV enzyme in a patient such as a mammal in need ofsuch inhibition comprising the administration of an effective amount ofthe compound. The present invention is directed to the use of thecompounds disclosed herein as inhibitors of dipeptidyl peptidase-IVenzyme activity.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals including, but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent, such as a mouse, species can be treated.However, the method can also be practiced in other species, such asavian species (e.g., chickens).

The present invention is further directed to a method for themanufacture of a medicament for inhibiting dipeptidyl peptidase-IVenzyme activity in humans and animals comprising combining a compound ofthe present invention with a pharmaceutically acceptable carrier ordiluent. More particularly, the present invention is directed to the useof a compound of structural formula I in the manufacture of a medicamentfor use in treating a condition selected from the group consisting ofhyperglycemia, Type 2 diabetes, obesity, and a lipid disorder in amammal, wherein the lipid disorder is selected from the group consistingof dyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, and high LDL.

The subject treated in the present methods is generally a mammal,preferably a human being, male or female, in whom inhibition ofdipeptidyl peptidase-IV enzyme activity is desired. The term“therapeutically effective amount” means the amount of the subjectcompound that will elicit the biological or medical response of atissue, system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention asinhibitors of dipeptidyl peptidase-IV enzyme activity may bedemonstrated by methodology known in the art. Inhibition constants aredetermined as follows. A continuous fluorometric assay is employed withthe substrate Gly-Pro-AMC, which is cleaved by DPP-IV to release thefluorescent AMC leaving group. The kinetic parameters that describe thisreaction are as follows: K_(m)=50 μM; k_(cat)=75 s⁻¹;k_(cat)/K_(m)=1.5×10⁶ M⁻¹ s⁻¹. A typical reaction contains approximately50 μM enzyme, 50 μM Gly-Pro-AMC, and buffer (100 mM HEPES, pH 7.5, 0.1mg/ml BSA) in a total reaction volume of 100 μl. Liberation of AMC ismonitored continuously in a 96-well plate fluorometer using anexcitation wavelength of 360 nm and an emission wavelength of 460 nm.Under these conditions, approximately 0.8 μM AMC is produced in 30minutes at 25 degrees C. The enzyme used in these studies was soluble(transmembrane domain and cytoplasmic extension excluded) human proteinproduced in a baculovirus expression system (Bac-To-Bac, Gibco BRL). Thekinetic constants for hydrolysis of Gly-Pro-AMC and GLP-1 were found tobe in accord with literature values for the native enzyme. To measurethe dissociation constants for compounds, solutions of inhibitor in DMSOwere added to reactions containing enzyme and substrate (final DMSOconcentration is 1%). All experiments were conducted at room temperatureusing the standard reaction conditions described above. To determine thedissociation constants (K_(i)), reaction rates were fit by non-linearregression to the Michaelis-Menton equation for competitive inhibition.The errors in reproducing the dissociation constants are typically lessthan two-fold.

In particular, the compounds of the following examples had activity ininhibiting the dipeptidyl peptidase-IV enzyme in the aforementionedassays, generally with an IC₅₀ of less than about 1 μM. Such a result isindicative of the intrinsic activity of the compounds in use asinhibitors the dipeptidyl peptidase-IV enzyme activity.

Dipeptidyl peptidase-IV enzyme (DPP-IV) is a cell surface protein thathas been implicated in a wide range of biological functions. It has abroad tissue distribution (intestine, kidney, liver, pancreas, placenta,thymus, spleen, epithelial cells, vascular endothelium, lymphoid andmyeloid cells, serum), and distinct tissue and cell-type expressionlevels. DPP-IV is identical to the T cell activation marker CD26, and itcan cleave a number of immunoregulatory, endocrine, and neurologicalpeptides in vitro. This has suggested a potential role for thispeptidase in a variety of disease processes in humans or other species.

Accordingly, the subject compounds are useful in a method for theprevention or treatment of the following diseases, disorders andconditions.

Type II Diabetes and Related Disorders: It is well established that theincretins GLP-1 and GIP are rapidly inactivated in vivo by DPP-IV.Studies with DPP-IV^((−/−))-deficient mice and preliminary clinicaltrials indicate that DPP-IV inhibition increases the steady stateconcentrations of GLP-1 and GIP, resulting in improved glucosetolerance. By analogy to GLP-1 and GIP, it is likely that other glucagonfamily peptides involved in glucose regulation are also inactivated byDPP-IV (e.g. PACAP). Inactivation of these peptides by DPP-IV may alsoplay a role in glucose homeostasis. The DPP-IV inhibitors of the presentinvention therefore have utility in the treatment of type II diabetesand in the treatment and prevention of the numerous conditions thatoften accompany Type II diabetes, including Syndrome X (also known asMetabolic Syndrome), reactive hypoglycemia, and diabetic dyslipidemia.Obesity, discussed below, is another condition that is often found withType II diabetes that may respond to treatment with the compounds ofthis invention.

The following diseases, disorders and conditions are related to Type 2diabetes, and therefore may be treated, controlled or in some casesprevented, by treatment with the compounds of this invention: (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) irritable bowel syndrome, (15) inflammatorybowel disease, including Crohn's disease and ulcerative colitis, (16)other inflammatory conditions, (17) pancreatitis, (18) abdominalobesity, (19) neurodegenerative disease, (20) retinopathy, (21)nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarianhyperandrogenism (polycystic ovarian syndrome), and other disorderswhere insulin resistance is a component. In Syndrome X, also known asMetabolic Syndrome, obesity is thought to promote insulin resistance,diabetes, dyslipidemia, hypertension, and increased cardiovascular risk.Therefore, DPP-IV inhibitors may also be useful to treat hypertensionassociated with this condition.

Obesity: DPP-IV inhibitors may be useful for the treatment of obesity.This is based on the observed inhibitory effects on food intake andgastric emptying of GLP-1 and GLP-2. Exogenous administration of GLP-1in humans significantly decreases food intake and slows gastric emptying(Am. J. Physiol., 277: R910-R916 (1999)). ICV administration of GLP-1 inrats and mice also has profound effects on food intake (Nature Medicine2: 1254-1258 (1996)). This inhibition of feeding is not observed inGLP-1R^((−/−)) mice, indicating that these effects are mediated throughbrain GLP-1 receptors. By analogy to GLP-1, it is likely that GLP-2 isalso regulated by DPP-IV. ICV administration of GLP-2 also inhibits foodintake, analogous to the effects observed with GLP-1 (Nature Medicine,6: 802-807 (2000)). In addition, studies with DPP-IV deficient micesuggest that these animals are resistant to diet-induced obesity andassociated pathology (e.g. hyperinsulinemia).Cardiovascular Disease: GLP-1 has been shown to be beneficial whenadministered to patients following acute myocardial infarction, leadingto improved left ventricular function and reduced mortality afterprimary angioplasty (Circulation, 109: 962-965 (2004)). GLP-1administration is also useful for the treatment of left ventricularsystolic dysfunction in dogs with dilated cardiomyopathy and ischemicinduced left ventricular dysfunction, and thus may prove useful for thetreatment of patients with heart failure (US2004/0097411). DPP-IVinhibitors are expected to show similar effects through their ability tostabilize endogenous GLP-1.Growth Hormone Deficiency: DPP-IV inhibition may be useful for thetreatment of growth hormone deficiency, based on the hypothesis thatgrowth-hormone releasing factor (GRF), a peptide that stimulates releaseof growth hormone from the anterior pituitary, is cleaved by the DPP-IVenzyme in vivo (WO 00/56297). The following data provide evidence thatGRF is an endogenous substrate: (1) GRF is efficiently cleaved in vitroto generate the inactive product GRF[3-44] (BBA 1122: 147-153 (1992));(2) GRF is rapidly degraded in plasma to GRF[3-44]; this is prevented bythe DPP-IV inhibitor diprotin A; and (3) GRF[3-44] is found in theplasma of a human GRF transgenic pig (J. Clin. Invest., 83: 1533-1540(1989)). Thus DPP-IV inhibitors may be useful for the same spectrum ofindications which have been considered for growth hormone secretagogues.Intestinal Injury: The potential for using DPP-IV inhibitors for thetreatment of intestinal injury is suggested by the results of studiesindicating that glucagon-like peptide-2 (GLP-2), a likely endogenoussubstrate for DPP-IV, may exhibit trophic effects on the intestinalepithelium (Regulatory Peptides 90: 27-32 (2000)). Administration ofGLP-2 results in increased small bowel mass in rodents and attenuatesintestinal injury in rodent models of colitis and enteritis.Immunosuppression: DPP-IV inhibition may be useful for modulation of theimmune response, based upon studies implicating the DPP-IV enzyme in Tcell activation and in chemokine processing, and efficacy of DPP-IVinhibitors in in vivo models of disease. DPP-IV has been shown to beidentical to CD26, a cell surface marker for activated immune cells. Theexpression of CD26 is regulated by the differentiation and activationstatus of immune cells. It is generally accepted that CD26 functions asa co-stimulatory molecule in in vitro models of T cell activation. Anumber of chemokines contain proline in the penultimate position,presumably to protect them from degradation by non-specificaminopeptidases. Many of these have been shown to be processed in vitroby DPP-IV. In several cases (RANTES, LD78-beta, MDC, eotaxin,SDF-1alpha), cleavage results in an altered activity in chemotaxis andsignaling assays. Receptor selectivity also appears to be modified insome cases (RANTES). Multiple N-terminally truncated forms of a numberof chemokines have been identified in in vitro cell culture systems,including the predicted products of DPP-IV hydrolysis.

DPP-IV inhibitors have been shown to be efficacious immunosuppressantsin animal models of transplantation and arthritis. Prodipine(Pro-Pro-diphenyl-phosphonate), an irreversible inhibitor of DPP-IV, wasshown to double cardiac allograft survival in rats from day 7 to day 14(Transplantation, 63: 1495-1500 (1997)). DPP-IV inhibitors have beentested in collagen and alkyldiamine-induced arthritis in rats and showeda statistically significant attenuation of hind paw swelling in thismodel [Int. J. Immunopharmacology, 19:15-24 (1997) andImmunopharmacology, 40: 21-26 (1998)]. DPP-IV is upregulated in a numberof autoimmune diseases including rheumatoid arthritis, multiplesclerosis, Graves' disease, and Hashimoto's thyroiditis (ImmunologyToday, 20: 367-375 (1999)).

HIV Infection: DPP-IV inhibition may be useful for the treatment orprevention of HIV infection or AIDS because a number of chemokines whichinhibit HIV cell entry are potential substrates for DPP-IV (ImmunologyToday 20: 367-375 (1999)). In the case of SDF-1alpha, cleavage decreasesantiviral activity (PNAS, 95: 6331-6 (1998)). Thus, stabilization ofSDF-1 alpha through inhibition of DPP-IV would be expected to decreaseHIV infectivity.Hematopoiesis: DPP-IV inhibition may be useful for the treatment orprevention of hematopoiesis because DPP-IV may be involved inhematopoiesis. A DPP-IV inhibitor, Val-Boro-Pro, stimulatedhematopoiesis in a mouse model of cyclophosphamide-induced neutropenia(WO 99/56753).Neuronal Disorders: DPP-IV inhibition may be useful for the treatment orprevention of various neuronal or psychiatric disorders because a numberof peptides implicated in a variety of neuronal processes are cleaved invitro by DPP-IV. A DPP-IV inhibitor thus may have a therapeutic benefitin the treatment of neuronal disorders. Endomorphin-2, beta-casomorphin,and substance P have all been shown to be in vitro substrates forDPP-IV. In all cases, in vitro cleavage is highly efficient, withk_(cat)/K_(m) about 10⁶ M⁻¹ s⁻¹ or greater. In an electric shock jumptest model of analgesia in rats, a DPP-IV inhibitor showed a significanteffect that was independent of the presence of exogenous endomorphin-2(Brain Research, 815: 278-286 (1999)). Neuroprotective andneuroregenerative effects of DPP-IV inhibitors were also evidenced bythe inhibitors' ability to protect motor neurons from excitotoxic celldeath, to protect striatal innervation of dopaminergic neurons whenadministered concurrently with MPTP, and to promote recovery of striatalinnervation density when given in a therapeutic manner following MPTPtreatment [see Yong-Q. Wu, et al., “Neuroprotective Effects ofInhibitors of Dipeptidyl Peptidase-IV In Vitro and In Vivo,” Int. Conf.On Dipeptidyl Aminopeptidases: Basic Science and Clinical Applications,Sep. 26-29, 2002 (Berlin, Germany)].Anxiety: Rats naturally deficient in DPP-IV have an anxiolytic phenotype(WO 02/34243; Karl et al., Physiol. Behav. 2003). DPP-IV deficient micealso have an anxiolytic phenotype using the porsolt and light/darkmodels. Thus DPP-IV inhibitors may prove useful for treating anxiety andrelated disorders.Memory and Cognition: GLP-1 agonists are active in models of learning(passive avoidance, Morris water maze) and neuronal injury(kainate-induced neuronal apoptosis) as demonstrated by During et al.(Nature Med. 9: 1173-1179 (2003)). The results suggest a physiologicalrole for GLP-1 in learning and neuroprotection. Stabilization of GLP-1by DPP-IV inhibitors are expected to show similar effects.Myocardial Infarction: GLP-1 has been shown to be beneficial whenadministered to patients following acute myocardial infarction(Circulation, 109: 962-965 (2004)). DPP-IV inhibitors are expected toshow similar effects through their ability to stabilize endogenousGLP-1.Tumor Invasion and Metastasis: DPP-IV inhibition may be useful for thetreatment or prevention of tumor invasion and metastasis because anincrease or decrease in expression of several ectopeptidases includingDPP-IV has been observed during the transformation of normal cells to amalignant phenotype (J. Exp. Med., 190: 301-305 (1999)). Up- ordown-regulation of these proteins appears to be tissue and cell-typespecific. For example, increased CD26/DPP-IV expression has beenobserved on T cell lymphoma, T cell acute lymphoblastic leukemia,cell-derived thyroid carcinomas, basal cell carcinomas, and breastcarcinomas. Thus, DPP-IV inhibitors may have utility in the treatment ofsuch carcinomas.Benign Prostatic Hypertrophy: DPP-IV inhibition may be useful for thetreatment of benign prostatic hypertrophy because increased DPP-IVactivity was noted in prostate tissue from patients with BPH (Eur. J.Clin. Chem. Clin. Biochem. 30: 333-338 (1992)).Sperm motility/male contraception: DPP-IV inhibition may be useful forthe altering sperm motility and for male contraception because inseminal fluid, prostatosomes, prostate derived organelles important forsperm motility, possess very high levels of DPP-IV activity (Eur. J.Clin. Chem. Clin. Biochem., 30: 333-338 (1992)).Gingivitis: DPP-IV inhibition may be useful for the treatment ofgingivitis because DPP-IV activity was found in gingival crevicularfluid and in some studies correlated with periodontal disease severity(Arch. Oral Biol., 37: 167-173 (1992)).Osteoporosis: DPP-IV inhibition may be useful for the treatment orprevention of osteoporosis because GIP receptors are present inosteoblasts.Stem Cell Transplantation: Inhibition of DPP-IV on donor stem cells hasbeen shown to lead to an enhancement of their bone marrow homingefficiency and engraftment, and an increase in survival in mice(Christopherson, et al., Science, 305:1000-1003 (2004)). Thus DPP-IVinhibitors may be useful in bone marrow transplantation.

The compounds of the present invention have utility in treating orpreventing one or more of the following conditions or diseases: (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) irritable bowel syndrome, (15) inflammatorybowel disease, including Crohn's disease and ulcerative colitis, (16)other inflammatory conditions, (17) pancreatitis, (18) abdominalobesity, (19) neurodegenerative disease, (20) retinopathy, (21)nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarianhyperandrogenism (polycystic ovarian syndrome), (25) Type II diabetes,(26) growth hormone deficiency, (27) neutropenia, (28) neuronaldisorders, (29) tumor metastasis, (30) benign prostatic hypertrophy,(31) gingivitis, (32) hypertension, (33) osteoporosis, and otherconditions that may be treated or prevented by inhibition of DPP-IV.

The subject compounds are further useful in a method for the preventionor treatment of the aforementioned diseases, disorders and conditions incombination with other agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, suppression oramelioration of diseases or conditions for which compounds of Formula Ior the other drugs may have utility, where the combination of the drugstogether are safer or more effective than either drug alone. Such otherdrug(s) may be administered, by a route and in an amount commonly usedtherefor, contemporaneously or sequentially with a compound of FormulaI. When a compound of Formula I is used contemporaneously with one ormore other drugs, a pharmaceutical composition in unit dosage formcontaining such other drugs and the compound of Formula I is preferred.However, the combination therapy may also include therapies in which thecompound of Formula I and one or more other drugs are administered ondifferent overlapping schedules. It is also contemplated that when usedin combination with one or more other active ingredients, the compoundsof the present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof Formula I.

Examples of other active ingredients that may be administered incombination with a compound of Formula I, and either administeredseparately or in the same pharmaceutical composition, include, but arenot limited to:

(a) other dipeptidyl peptidase IV (DPP-IV) inhibitors;

(b) insulin sensitizers including (i) PPARγ agonists, such as theglitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555,rosiglitazone, balaglitazone, and the like) and other PPAR ligands,including PPARα/γ dual agonists, such as KRP-297, muraglitazar,naveglitazar, tesaglitazar, TAK-559, PPARα agonists, such as fenofibricacid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate),and selective PPARγ modulators (SPPARγM's), such as disclosed in WO02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408,and WO 2004/066963; (ii) biguanides such as metformin and phenformin,and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(c) insulin or insulin mimetics;

(d) sulfonylureas and other insulin secretagogues, such as tolbutamide,glyburide, glipizide, glimepiride, and meglitinides, such as nateglinideand repaglinide;

(e) α-glucosidase inhibitors (such as acarbose and miglitol);

(f) glucagon receptor antagonists, such as those disclosed in WO97/16442; WO 98/04528, WO 98/21957; WO 98/22108; WO 98/22109; WO99/01423, WO 00/39088, and WO 00/69810; WO 2004/050039; and WO2004/069158;

(g) GLP-1, GLP-1 analogues or mimetics, and GLP-1 receptor agonists,such as exendin-4 (exenatide), liraglutide (N,N-2211), CJC-1131,LY-307161, and those disclosed in WO 00/42026 and WO 00/59887;

(h) GIP and GIP mimetics, such as those disclosed in WO 00/58360, andGIP receptor agonists;

(i) PACAP, PACAP mimetics, and PACAP receptor agonists such as thosedisclosed in WO 01/23420;

(j) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin,atorvastatin, itavastatin, and rosuvastatin, and other statins), (ii)sequestrants (cholestyramine, colestipol, and dialkylaminoalkylderivatives of a cross-linked dextran), (iii) nicotinyl alcohol,nicotinic acid or a salt thereof, (iv) PPARα agonists such as fenofibricacid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate),(v) PPARα/γ dual agonists, such as naveglitazar and muraglitazar, (vi)inhibitors of cholesterol absorption, such as beta-sitosterol andezetimibe, (vii) acyl CoA:cholesterol acyltransferase inhibitors, suchas avasimibe, and (viii) antioxidants, such as probucol;

(k) PPARδ agonists, such as those disclosed in WO 97/28149;

(l) antiobesity compounds, such as fenfluramine, dexfenfluramine,phentermine, sibutramine, orlistat, neuropeptide Y₁ or Y₅ antagonists,CB1 receptor inverse agonists and antagonists, β₃ adrenergic receptoragonists, melanocortin-receptor agonists, in particular melanocortin-4receptor agonists, ghrelin antagonists, bombesin receptor agonists (suchas bombesin receptor subtype-3 agonists), and melanin-concentratinghormone (MCH) receptor antagonists;

(m) ileal bile acid transporter inhibitors;

(n) agents intended for use in inflammatory conditions such as aspirin,non-steroidal anti-inflammatory drugs (NSA/Ds), glucocorticoids,azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors;

(o) antihypertensive agents, such as ACE inhibitors (enalapril,lisinopril, captopril, quinapril, tandolapril), A-II receptor blockers(losartan, candesartan, irbesartan, valsartan, telmisartan, andeprosartan), beta blockers and calcium channel blockers;

(p) glucokinase activators (GKAs), such as those disclosed in WO03/015774; WO 04/076420; and WO 04/081001;

(q) inhibitors of 11β-hydroxysteroid dehydrogenase type 1, such as thosedisclosed in U.S. Pat. No. 6,730,690; WO 03/104207; and WO 04/058741;

(r) inhibitors of cholesteryl ester transfer protein (CETP), such astorcetrapib; and

(s) inhibitors of fructose 1,6-bisphosphatase, such as those disclosedin U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and6,489,476.

Dipeptidyl peptidase-IV inhibitors that can be combined with compoundsof structural formula I include those disclosed in U.S. Pat. No.6,699,871; WO 02/076450 (3 Oct. 2002); WO 03/004498 (16 Jan. 2003); WO03/004496 (16 Jan. 2003); EP 1 258 476 (20 Nov. 2002); WO 02/083128 (24Oct. 2002); WO 02/062764 (15 Aug. 2002); WO 03/000250 (3 Jan. 2003); WO03/002530 (9 Jan. 2003); WO 03/002531 (9 Jan. 2003); WO 03/002553 (9Jan. 2003); WO 03/002593 (9 Jan. 2003); WO 03/000180 (3 Jan. 2003); WO03/082817 (9 Oct. 2003); WO 03/000181 (3 Jan. 2003); WO 04/007468 (22Jan. 2004); WO 04/032836 (24 Apr. 2004); WO 04/037169 (6 May 2004); andWO 04/043940 (27 May 2004). Specific DPP-IV inhibitor compounds includeisoleucine thiazolidide (P32/98); NVP-DPP-728; vildagliptin (LAF 237);P93/01; and saxagliptin (BMS 477118).

Antiobesity compounds that can be combined with compounds of structuralformula I include fenfluramine, dexfenfluramine, phentermine,sibutramine, orlistat, neuropeptide Y₁ or Y₅ antagonists, cannabinoid CB1 receptor antagonists or inverse agonists, melanocortin receptoragonists, in particular, melanocortin-4 receptor agonists, ghrelinantagonists, bombesin receptor agonists, and melanin-concentratinghormone (MCH) receptor antagonists. For a review of anti-obesitycompounds that can be combined with compounds of structural formula I,see S. Chaki et al., “Recent advances in feeding suppressing agents:potential therapeutic strategy for the treatment of obesity,” ExpertOpin. Ther. Patents, 11: 1677-1692 (2001); D. Spanswick and K. Lee,“Emerging antiobesity drugs,” Expert Opin. Emerging Drugs, 8: 217-237(2003); and J. A. Fernandez-Lopez, et al., “Pharmacological Approachesfor the Treatment of Obesity,” Drugs, 62: 915-944 (2002).

Neuropeptide Y5 antagonists that can be combined with compounds ofstructural formula I include those disclosed in U.S. Pat. No. 6,335,345(1 Jan. 2002) and WO 01/14376 (1 Mar. 2001); and specific compoundsidentified as GW 59884A; GW 569180A; LY366377; and CGP-71683A.

Cannabinoid CB 1 receptor antagonists that can be combined withcompounds of formula I include those disclosed in PCT Publication WO03/007887; U.S. Pat. No. 5,624,941, such as rimonabant; PCT PublicationWO 02/076949, such as SLV-319; U.S. Pat. No. 6,028,084; PCT PublicationWO 98/41519; PCT Publication WO 00/10968; PCT Publication WO 99/02499;U.S. Pat. No. 5,532,237; U.S. Pat. No. 5,292,736; PCT Publication WO03/086288; PCT Publication WO 03/087037; PCT Publication WO 04/048317;PCT Publication WO 03/007887; PCT Publication WO 03/063781; PCTPublication WO 03/075660; PCT Publication WO 03/077847; PCT PublicationWO 03/082190; PCT Publication WO 03/082191; PCT Publication WO03/087037; PCT Publication WO 03/086288; PCT Publication WO 04/012671;PCT Publication WO 04/029204; PCT Publication WO 04/040040; PCTPublication WO 01/64632; PCT Publication WO 01/64633; and PCTPublication WO 01/64634.

Melanocortin-4 receptor (MC4R) agonists useful in the present inventioninclude, but are not limited to, those disclosed in U.S. Pat. No.6,294,534, U.S. Pat. Nos. 6,350,760, 6,376,509, 6,410,548, 6,458,790,U.S. Pat. No. 6,472,398, U.S. Pat. No. 5,837,521, U.S. Pat. No.6,699,873, which are hereby incorporated by reference in their entirety;in US Patent Application Publication Nos. US 2002/0004512,US2002/0019523, US2002/0137664, US2003/0236262, US2003/0225060,US2003/0092732, US2003/109556, US 2002/0177151, US 2002/187932, US2003/0113263, which are hereby incorporated by reference in theirentirety; and in WO 99/64002, WO 00/74679, WO 02/15909, WO 01/70708, WO01/70337, WO 01/91752, WO 02/068387, WO 02/068388, WO 02/067869, WO03/007949, WO 2004/024720, WO 2004/089307, WO 2004/078716, WO2004/078717, WO 2004/037797, WO 01/58891, WO 02/070511, WO 02/079146, WO03/009847, WO 03/057671, WO 03/068738, WO 03/092690, WO 02/059095, WO02/059107, WO 02/059108, WO 02/059117, WO 02/085925, WO 03/004480, WO03/009850, WO 03/013571, WO 03/031410, WO 03/053927, WO 03/061660, WO03/066597, WO 03/094918, WO 03/099818, WO 04/037797, WO 04/048345, WO02/018327, WO 02/080896, WO 02/081443, WO 03/066587, WO 03/066597, WO03/099818, WO 02/062766, WO 03/000663, WO 03/000666, WO 03/003977, WO03/040107, WO 03/040117, WO 03/040118, WO 03/013509, WO 03/057671, WO02/079753, WO 02/092566, WO 03/-093234, WO 03/095474, and WO 03/104761.

The potential utility of safe and effective activators of glucokinase(GKAs) for the treatment of diabetes is discussed in J. Grimsby et al.,“Allosteric Activators of Glucokinase: Potential Role in DiabetesTherapy,” Science, 301: 370-373 (2003).

When a compound of the present invention is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound of the present invention ispreferred. Accordingly, the pharmaceutical compositions of the presentinvention include those that also contain one or more other activeingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith another agent, the weight ratio of the compound of the presentinvention to the other agent will generally range from about 1000:1 toabout 1:1000, preferably about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed.(For purposes of this application, topical application shall includemouthwashes and gargles.)

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment or prevention of conditions which require inhibition ofdipeptidyl peptidase-IV enzyme activity an appropriate dosage level willgenerally be about 0.01 to 500 mg per kg patient body weight per daywhich can be administered in single or multiple doses. Preferably, thedosage level will be about 0.1 to about 250 mg/kg per day; morepreferably about 0.5 to about 100 mg/kg per day. A suitable dosage levelmay be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day,or about 0.1 to 50 mg/kg per day. Within this range the dosage may be0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration,the compositions are preferably provided in the form of tabletscontaining 1.0 to 1000 mg of the active ingredient, particularly 1.0,5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0,300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

When treating or preventing diabetes mellitus and/or hyperglycemia orhypertriglyceridemia or other diseases for which compounds of thepresent invention are indicated, generally satisfactory results areobtained when the compounds of the present invention are administered ata daily dosage of from about 0.1 mg to about 100 mg per kilogram ofanimal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Formost large mammals, the total daily dosage is from about 1.0 mg to about1000 mg, preferably from about 1 mg to about 50 mg. In the case of a 70kg adult human, the total daily dose will generally be from about 7 mgto about 350 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Synthetic methods for preparing the compounds of the present inventionare illustrated in the following Schemes and Examples. Startingmaterials are commercially available or may be made according toprocedures known in the art or as illustrated herein.

The compounds of the present invention can be prepared, by variousmodifications, starting from amino heterocyclic intermediates of formulaII and α,β-unsaturated nitrile intermediates such as those of thegeneral formula III. The preparation of these intermediates and theirconversion to compounds of formula I are described in the followingschemes.

wherein A, R¹, and Z are defined as defined above; Y is CN or C(S)NH₂,and X is H or a leaving group.

Compounds of formula II are commercially available, known in theliterature, or may be conveniently prepared by a variety of methodsfamiliar to those skilled in the art. One common route to II wherein Ais N is illustrated in Scheme 1. Aminoguanidine (1) is reacted with anacid or acid derivative 2, in which L is a leaving group [e.g., R¹(CO)Lis a carboxylic acid, ester, acid anhydride, or acid chloride] or withan iminoether 3 (R is typically methyl or ethyl) with heating to givethe aminotriazole II. Useful references for this transformation include:F. Kurzer and L. E. A. Godfrey, Angew. Chem., 75, 1157 (1963); S. C.Bell, U.S. Pat. No. 4,347,362 (1982); C. A. Lipinski et al., J. Med.Chem., 28, 1628 (1985); V. V. Kiseleva et al., Izv. Akad. Nauk SSSR,Ser. Khim., 2075 (1990); A. A. Abdel-Hafez et al., Arztzeim.-Forsch.,52, 833 (2002); and T. Akbarzadeh et al., Bioorg. Med. Chem., 11, 769(2003).

As illustrated in Scheme 2, aminotriazoles of formula II (A=N) in whichR¹ is of the formula R⁴O—, R⁴S—, or R⁵R⁶N— may be convenientlysynthesized by reaction of hydrazine with an appropriateN-cyanoazomethine 4, in which X is a leaving group such as methoxy,ethoxy, or methylthio [B. T. Heitke and C. G. McCarty, J. Org. Chem.,39, 1522 (1974)].

A general route to intermediates of formula II wherein A is CR² is shownin Scheme 3. A nitrile derivative of structure 5 is treated with asuitable strong base (e.g., potassium tert-butoxide, butyllithium,sodium amide, or sodium hydride) to form the anion and then treated withan ester 6 (or related derivative) to give the acylated product 7, whichis in equilibrium with the enol form 8. Subsequent reaction withhydrazine, for example, in ethanol at reflux, affords the aminopyrazoleof structure II. Useful references for this transformation include: E.L. Anderson et al., J. Med. Chem., 7, 259 (1964); K. Takahashi et al.,Synthesis, 794 (1985); E. Lunt et al., J. Med. Chem., 30, 357 (1987); D.Fouque et al., Synth. Commun., 25, 3443 (1995); T. Honma et al., J. Med.Chem., 44, 4628 (2001); N. Sato et al., J. Med. Chem., 46, 666 (2003).Similar syntheses via enol ethers or enamines analogous to 8 are alsowell known [e.g., H. Baganz et al., Chem. Ber., 98, (1965); E. Alcade etal., J. Heterocycl. Chem., 11, 423 (1974); K. M. Dawood et al., J. Chem.Res. (S), 208 (1998); and V. N. Belov et al., Eur. J. Org. Chem., 551(2003)].

As shown in Scheme 4, condensation of malononitrile (9) with aldehyde10, typically run in an alcoholic solvent in the presence of a catalystsuch as piperidine, affords intermediate m (X═H, Y═CN) [see, forexample: M. Boehringer et al. WO 03/068757 (2003); A. M. Shestapalov etal., Chem. Heterocycl. Compd. (Engl. Transl. of Khim. Geterotsikl.Soedin.), 38, 1345 (2002); A. J. Fatiadi, Synthesis, 165 (1978); R. F.Silver et al., Can. J. Chem., 45, 1001 (1967)]. Similar condensation of9 with 2-cyanothioacetamide (11) gives III [X═H, Y═C(S)NH₂] [J. S. A.Brunskill and A. De, J. Chem. Soc. Perkin Trans. 1, 629 (1978)].Reaction of 9 with acid chloride 12 in the presence of a tertiary aminesuch as N,N-diisopropylethylamine provides adduct 13, which may bemethylated with diazomethane or (trimethylsilyl)diazomethane to yieldIII (X═OMe, Y═CN) [see, for example, G. C. Hirst et al. US 2002/0156081;T. Aoyama et al., Chem. Pharm. Bull., 32, 3759 (1984)]. Analogous III(Y═CN) in which the leaving group X═SMe or NR₂ may also be prepared[see, for example, Y. Tominaga et al., Heterocycles, 26, 613 (1987); Y.Tominaga et al., J. Heterocycl. Chem., 27, 647 (1990)].

As shown in Scheme 5, an aminoheterocycle of formula II may be reactedwith an α,β-unsaturated nitrile of formula III (X═H, Y═CN) to giveinitially a fused dihydropyrimidine of structure 14 (or tautomer) [J. J.Vaquero et al., Synthesis, 33 (1987); W. Ried and S. Aboul-Fetouh,Tetrahedron, 44, 7155 (1988)]. Typically this reaction is carried out ina high-boiling solvent such as pyridine or N,N-dimethylformamide atreflux. Usually 14 is not isolated. Instead, on continued heating inair, spontaneous oxidation to the aromatic heterocycle 15 generallyoccurs [see, for example: A. M. S. Youssef et al., J. Korean Chem. Soc.,45, 448 (2001); A. A. Hassanien et al., J. Chinese Chem. Soc., 47, 1273(2000); F. M. Abdelrazek, J. Prakt. Chem., 331, 475 (1989); S. A. S.Ghozlan and A. Z. A. Hassanian, Tetrahedron, 58, 9423 (2002); M. H.Elnagdi et al., Collect. Czech. Chem. Commun., 54, 1082 (1989); A.Al-Enzy et al., J. Chem. Res. (M), 116 (1997)]. In some instances wherethe air oxidation does not proceed satisfactorily, an oxidizing agentsuch as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) may be added,and the mixture is either stirred at ambient temperature [J. J. Vaqueroet al., Synthesis, 33 (1987)] or heated to drive the oxidation tocompletion. The cyano group of 15 may be reduced to aminomethyl byvarious methods, depending on the compatibility of functional groups inthe molecule. Scheme 5 shows the convenient reduction byborane-tetrahydrofuran complex. The amine may be liberated from theresulting amine-borane complex by treatment with methanol and excessconcentrated aqueous hydrochloric acid, with heating as necessary. Thisyields the product of formula I. Reaction of II with higher oxidationstate III (X═OMe, SMe, or NH₂, etc.) under similar conditions may give15 directly [see, for example: Y. Tominaga et al., Chem. Pharm. Bull.,33, 962 (1985); W. Ried and S. Aboul-Fetouh, Tetrahedron, 44, 7155(1988); A. G. A. Elagamey and F. M. A.-A. El-Taweel, J. Prakt. Chem.,333, 333 (1991)]. In most cases, however, superior yields of 15 where Zis aryl or heteroaryl are obtained by use of III (X═H) as shown inScheme 5. Also, 2-cyanothioacetamide-derived III [X═H, Y═C(S)NH₂] hasbeen used in place of malononitrile-derived III (X═H, Y═CN) to obtainintermediates of general structure 15 [S. M. Hussain et al.,Tetrahedron, 44, 241 (1988); S. M. Hussain et al., Indian J. Chem., 27B,421 (1988).

It should be noted that condensation of II with III may give more thanone regioisomeric product and that 15 may not always be the majorisomer. In reactions of this type, aspects of regioisomerism andspectral methods for structure assignments have been discussed in theliterature [see, for example: A. M. S. Youssef et al., J. Korean Chem.Soc., 45, 448 (2001); A. A. Hassanien et al., J. Chinese Chem. Soc., 47,1273 (2000); M. H. Elnagdi et al., Collect. Czech. Chem. Commun., 54,1082 (1989)]. Furthermore, in the case of aminotriazole startingmaterials of formula II, any 1,2,4-triazolo[4,3-a]pyrimidine isomer thatforms during the condensation reaction may rearrange to the generallymore stable 1,2,4-triazolo[1,5-a]pyrimidine isomer (i.e., formula I,A=N) during the acidic work-up of the subsequent borane reduction. Suchrearrangements are well documented in the literature [D. J. Brown and T.Nagamatsu, Aust. J. Chem., 30, 2515 (1977); H. S. El Khadem et al.,Heterocycles, 28, 239 (1989)].

Scheme 6 illustrates some representative but non-limiting methods forthe synthesis of compounds of formula I wherein W¹ and/or W²═C₁₋₄ alkyl.It is first advantageous to fully protect the primary amino group of 15.This may be accomplished by treating 15 with sodium hydride and anexcess of arylmethyl halide 16 (e.g., 4-methoxybenzyl chloride or benzylbromide) in an anhydrous polar solvent such as dimethyl sulfoxide orN,N-dimethylformamide [for analogous alkylation, see S. Kataoka et al.,Chem. Pharm. Bull., 38, 3147 (1990); G. B. Evans et al., J. Org. Chem.,69, 2217 (2004)]. Alternatively, 17 may be prepared by a different routein which the amino group is introduced in a protected form. Thus, ethylcyanoacetate is condensed with aldehyde 10 under conditions similar tothose in Scheme 4 to give the adduct 19. In analogy to the synthesis of15 from II and III (X═H) as in Scheme 5, 19 can be condensed with anamino heterocycle of formula II in the presence of air to afford thefused pyrimidinol 20 [see, for example: M. H. Elnagdi et al., Collect.Czech. Chem. Commun., 54, 1082 (1989); F. M. Abdelrazek, J. Prakt.Chem., 331, 475 (1989); F. M. Abdelrazek et al., Egypt. J. Chem., 42, 75(1999); A. A. Hassanien et al., J. Chinese Chem. Soc., 47, 1273 (2000)].Treatment of 20 with phosphorus oxychloride (usually at elevatedtemperature and optionally in the presence of a tertiary amine such asN,N-dimethylaniline) affords the chloro heterocycle 21 [see, forexample, reports of analogous preparations: W. A. Kleshick and J.Bordner, J. Heterocycl. Chem., 26, 1489 (1989); Y. Tominaga et al.,Chem. Pharm. Bull., 33, 962 (1985); T. Novinson et al., J. Med. Chem.,25, 420 (1982); J. S. Bajwa and P. J. Sykes, J. Chem. Soc. Perkin Trans1, 3085 (1979)]. Subsequent displacement of the chloro group of 21 bythe bis(arylmethyl)amine 22 [e.g., bis(4-methoxybenzyl)amine,bis(2,4-dimethoxybenzylamine) or dibenzylamine)] yields 17 [for similarreactions, see: V. Mesguiche et al., Bioorg. Med. Chem. Lett., 13, 217(2003); M. J. Krische et al., Helv. Chim. Acta, 81, 1921 (1998); G.Berecz et al., J. Heterocycl. Chem., 39, 703 (2002); Y. Tominaga et al.,Chem. Pharm. Bull., 33, 962 (1985); T. Novinson et al., J. Med. Chem.,25, 420 (1982)]. Addition of a Grignard reagent W¹MgBr, W¹MgCl, or W¹MgIto the nitrile group of 17 followed by reduction of the intermediateimine with sodium borohydride in methanol [E. Leclerc et al., J. Org.Chem., 67, 8928 (2002)] provides the amine 23 bearing a monoalkylsubstituent at the adjacent carbon. Reaction of 17 with threeequivalents of an alkylcerium dichloride W¹CeCl₂ [prepared in situ bylow temperature addition of an alkyllithium W¹Li (e.g., methyllithium)to dry cerium(III) chloride] provides the gem-disubstituted derivative24 [for similar examples, see: E. Ciganek, J. Org. Chem., 57, 4521(1992); V. Fedij et al., Tetrahedron: Asymmetry, 5, 1131 (1994); V.Fedij et al., U.S. Pat. No. 5,347,017 (1994)]. Also, reaction of 17 withethylmagnesium bromide in the presence of titanium tetraisopropoxidefollowed by treatment with boron trifluoride etherate [P. Bertus and J.Szymoniak, J. Org. Chem., 67, 3965 (2002); P. Bertus and J. Szymoniak,Synlett., 265 (2003)] affords the 1-aminocyclopropyl derivative 25. Arelated synthesis of 1-aminocyclopropyl derivatives using diethylzinc[S. Wiedemann et al., Org. Lett., 5, 753 (2003)] may also be employed.Finally, the intermediates 23-25 are deprotected to yield the compoundsof formula I. Some analogous deprotections have been carried out with(1) trifluoroacetic acid at 60° C. [for Ar=4-methoxyphenyl: V. Mesguicheet al., Bioorg. Med. Chem. Lett., 13, 217 (2003)], (2) a mixture ofconcentrated hydrochloric acid and methanol at reflux [forAr=4-methoxyphenyl: G. B. Evans et al., J. Med. Chem., 46, 5271 (2003)],(3) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) [forAr=2,4-dimethoxyphenyl: M. J. Krische et al., Helv. Chim. Acta, 81, 1921(1998)], or (4) trifluoromethanesulfonic acid in dichloromethane at 40°C. [for Ar=phenyl: D. L. Boger et al., J. Org. Chem., 57, 4333 (1992)].

The amine of formula I is purified from unwanted side products, ifnecessary, by recrystallization, trituration, preparative thin layerchromatography, flash chromatography on silica gel as described by W. C.Still et al, J. Org. Chem., 43, 2923 (1978), or HPLC. Compounds whichare purified by HPLC may be isolated as the corresponding salt.Purification of intermediates is achieved in the same manner.

In some cases the intermediates or final products may be furthermodified, for example, by manipulation of R¹ and/or R² substituents.These manipulations may include, but are not limited to, reduction,oxidation, alkylation, acylation, and hydrolysis reactions which arecommonly known to those skilled in the art. Examples of a few of thesetransformations are illustrated in Schemes 7 and 8 below.

One example of functional group transformations is shown in Scheme 7.Thus, the methylthio substituent of 26 may be oxidized to thecorresponding sulfone 27 by m-chloroperoxybenzoic acid. Intermediates 26and 27 may then be individually reduced, as in Scheme 5, to the targetcompounds I-c and I-d, respectively.

Scheme 8 shows how some substituent functional groups may be furthertransformed during the reduction of the nitrile. Thus, 28, whichcontains an ester substituent on the pyrazolo moiety, may yield multipleproducts from the borane reduction, including unchanged ester I-e,hydroxymethyl I-f, and methyl I-g. Similarly, the attached pyrazine ringof 29 and the fused pyridine ring of 30 may be reduced at the same timeas the nitrile to yield I-h and I-i, respectively.

Various additional functional group manipulations may be carried out,and these will be known to persons skilled in the art.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way.

(2,4-Dichlorobenzylidene)malononitrile

This material was prepared from malononitrile and2,4-dichlorobenzaldehyde according to the procedure of M. Boehringer etal., WO 03/068748.

(2,4-Dimethylbenzylidene)malononitrile

This material was prepared from malononitrile and2,4-dimethylbenzaldehyde according to the procedure of M. Boehringer etal., WO 03/068748.

(Mesitylmethylene)malononitrile

In analogy to the methods described by M. Boehringer et al., WO03/068748, a solution of 25 g (169 mmol) of mesitaldehyde(2,4,6-trimethylbenzaldehyde) and 13.5 g (204 mmol) of malononitrile in70 mL of n-butanol was stirred at room temperature for 1 h and thentreated dropwise with 0.4 mL of piperidine, resulting in a color changeand precipitation. After 5 h, the mixture was cooled in a freezer (−20°C.) for 10 min and then filtered. The solid was washed three times withcold n-butanol and then dried to give the title compound as a whitesolid. LC-MS 197 (M+1). This material has been reported as being made bya similar procedure [A. M. Shestapalov et al., Chem. Heterocycl. Compd.(Engl. Transl. of Khim. Geterotsikl. Soedin.), 38, 1345 (2002)].

[(3,5-Dichloropyridin-2-yl)methylene]malononitrile

By the method used for Intermediate3,3,5-dichloropyridine-2-carbaldehyde (R. Bonjouklian et al., WO02/081482) and malononitrile were reacted to give the title compound asa dark greenish powder. LC-MS 224 (M+1).

(2,4,6-Trichlorobenzylidene)malononitrile

By the method used for Intermediate 3,2,4,6-trichlorobenzaldehyde [S.Banfi et al., J. Chem. Soc. Perkin Trans. 2, 871 (2000)] andmalononitrile were reacted to give the title compound as a pinkishsolid. LC-MS 257 (M+1).

(4-Chloro-2-methoxybenzylidene)malononitrile Step A4-Chloro-2-methoxybenzaldehyde

Following the general method of R. A. Miller and R. S. Hoerrner, Org.Lett., 5, 285 (2003), a solution of 2.5 g (14.1 mmol based on 97%purity) of 4-chloro-2-methoxybenzyl alcohol in 35 mL of toluene wastreated with 35 mL of water and 3.54 g (42.3 mmol) of sodiumbicarbonate. The resulting two-phase mixture was stirred at ambienttemperature as 7.2 g (28.2 mmol) of iodine was added, followed by 0.223g (1.41 mmol) of 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical(TEMPO). After 3 days, the dark mixture was cooled to 5° C. and quenchedby addition of a solution of 1.8 g of sodium sulfite in 18 mL of water.The mixture was partitioned between ethyl acetate and water. The organiclayer was washed with saturated aqueous sodium bicarbonate solution andthen with brine. The organic phase was then dried over anhydrous sodiumsulfate. The supernatant was concentrated to a volume of approximately 5mL and kept at 5° C. for 1 h. The solid that separated was collected ona filter, washed twice with small volumes of cold toluene, and dried invacuo to yield the title compound as a white solid. LC-MS 171 (M+1).

Step B (4-Chloro-2-methoxybenzylidene)malononitrile

By the method used for Intermediate 3,4-chloro-2-methoxybenzaldehydefrom Step A was reacted with malononitrile to afford the title compoundas a yellow solid. LC-MS 219 (M+1).

Additional substituted benzylidenemalononitrile derivatives (Table 1)were prepared by the procedures described above for Intermediates 1-6.

TABLE 1

Mass Spectrum Intermediate Ar (M + 1) 7 2-F-4-Cl—Ph 207 8 2-Me-4-Cl—Ph203 9 2-F-4-CF₃—Ph 241 10 2,3-F₂-4-Me—Ph 205 11 2,4,5-F₃—Ph 209 122,4-Cl₂-6-MeO—Ph 253

5-(Trifluoromethyl)-1H-1,2,4-triazol-3-amine

The title compound was prepared by the procedure of V. A. Lopyrev and T.N. Rakbmatulina, J. Gen. Chem. USSR (Engl. Transl. of Zh. Obshch.Khim.), 53, 1684 (1983).

(3-Amino-1H-1,2,4-triazol-5-yl)methanol

The title compound was prepared by the procedure of N. Bru-Mahniez etal., U.S. Pat. No. 5,387,747 (1995).

5-Pyrazin-2-yl-1H-1,2,4-triazol-3-amine

The title compound was prepared by the general method of H. L. Yale andJ. J. Piala, J. Med. Chem., 9, 42 (1966).

5-Amino-2,4-dihydro-3H-1,2,4-triazol-3-one(3-Amino-1H-1,2,4-triazol-5-ol)

The title compound was prepared according to the procedure of L. E. A.Godfrey and F. Kurzer, J. Chem. Soc., 3437 (1960).

4-(Methylsulfonyl)-1H-pyrazol-3-amine

The title compound was prepared by the procedure of E. Lunt et al., J.Med. Chem., 30, 357 (1987).

4-Pyridin-4-yl-1H-pyrazol-3-amine

The title compound was prepared by the procedure of M. E. Fraley et al.,Bioorg. Med. Chem. Lett., 12, 2767 (2002).

4-Pyridin-3-yl-1H-pyrazol-3-amine

The title compound was prepared by the procedure of M. E. Fraley et al.,Bioorg. Med. Chem. Lett., 12, 2767 (2002).

4-Pyridin-2-yl-1H-pyrazol-3-amine

The title compound was prepared by the procedure of M. E. Fraley et al.,Bioorg. Med. Chem. Lett., 12, 2767 (2002).

4-(4-Methyl-1,3-thiazol-2-yl)-1H-pyrazol-3-amine

The title compound was prepared in analogy to Intermediates 18-20 by themethod of M. E. Fraley et al., Bioorg. Med. Chem. Lett., 12, 2767(2002).

4,6-Dihydro-1H-thieno[3,4-c]pyrazol-3-amine

To a suspension of 1.00 g (7.86 mmol) of 4-cyanotetrahydrothiophenone in6 mL of ethanol was added 0.275 mL (286 mg, 4.76 mmol) of glacial aceticacid, followed by 0.475 mL (489 mg, 9.77 mmol) of hydrazine hydrate. Theresulting clear solution was stirred overnight under nitrogen withheating in an oil bath at 80° C. The cooled reaction mixture was thenpartitioned between ethyl acetate and saturated sodium bicarbonateaqueous solution. The aqueous phase was re-extracted with an additionalportion of ethyl acetate. The combined organic fractions were washedwith saturated sodium chloride aqueous solution, then dried overanhydrous sodium sulfate, filtered, and concentrated to a syrup.Trituration of this oil with dichloromethane containing a small amount(less than 3%) of methanol resulted in crystallization. The suspensionwas heated to gentle reflux for a few minutes and then cooled. The solidwas collected on a filter and washed with a small volume ofdichloromethane to yield the title compound as almost colorlesscrystals. LC-MS 142 (M+1).

5-Methoxy-1H-1,2,4-triazol-3-amine

The title compound was prepared according to the procedure of B. T.Heitke and C. G. McCarty, J. Org. Chem., 39, 1522 (1974).

4-Methoxy-1H-pyrazol-3-amine

The title compound was prepared according to the procedure of T. Okazakiet al., U.S. Pat. No. 5,475,114 (1995).

Example 1

6-(Aminomethyl)-5-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,Trifluoroacetic Acid Salt Step A7-Amino-5-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile

A solution of 157 mg (1.87 mmol) of 3-amino-1,2,4-triazole and 417 mg(1.87 mmol) of (2,4-dichlorobenzylidene)malononitrile (Intermediate 1)in 4.7 mL of anhydrous pyridine was stirred at reflux under air for 22 hand then cooled and concentrated in vacuo. The residue was partitionedbetween 5% aqueous citric acid solution and a 1:1 mixture of ethylacetate and tetrahydrofuran. The organic phase was washed once more withthe citric acid solution and then (after addition of some moretetrahydrofuran) with saturated aqueous sodium chloride solution. Thecombined aqueous fractions were re-extracted with a 2:3 mixture of ethylacetate and tetrahydrofuran. The combined organics were dried overmagnesium sulfate, filtered, and concentrated in vacuo. Purification ofthe residue by flash chromatography on silica gel (gradient elution with2-3% methanol in dichloromethane) afforded the title compound as anamber-colored glass, which was used without further purification. LC-MS305 (M+1).

Step B6-(Aminomethyl)-5-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine-7-amine,Trifluoroacetic Acid Salt

A solution of 73.2 mg (0.24 mmol) of7-amino-5-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrilefrom Step A in 1.2 mL of anhydrous tetrahydrofuran was stirred undernitrogen at ambient temperature as 1.2 mL (1.2 mmol) of 1Mborane-tetrahydrofuran complex in tetrahydrofuran was added dropwise bysyringe over about 10 min. After 7 h, the mixture was quenched bycautious dropwise addition of 0.36 mL (4.32 mmol) of concentratedhydrochloric acid (gas evolution) followed by addition of 1.2 mL ofmethanol. After being stirred overnight at ambient temperature, thesolution was transferred to a sealed tube and stirred with heating in anoil bath at 80° C. for 6 h. The solution was then evaporated to dryness.Purification of the residue by preparative HPLC (C18 reverse phasecolumn, gradient elution with 2-75% acetonitrile in water containing0.05% trifluoroacetic acid) yielded the title compound as a glass. LC-MS309 (M+1).

Example 2

6-(Aminomethyl)-5-(2,4-dichlorophenyl)-2-(methylthio)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,Trifluoroacetic Acid Salt Step A7-Amino-5-(2,4-dichlorophenyl)-2-(methylthio)[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile

According to the procedure of Example 1, Step A, commercial5-(methylthio)-1H-1,2,4-triazol-3-amine and(2,4-dichlorobenzylidene)malononitrile (Intermediate 1) were reacted togive the title compound as a dark brown solid. LC-MS 351 (M+1).

Step B6-(Aminomethyl)-5-(2,4-dichlorophenyl)-2-(methylthio)[1,2,4]triazolo[1,5-a]pyrimidin-7-amineTrifluoroacetic Acid Salt

Essentially by the procedure of Example 1, Step B,7-amino-5-(2,4-dichlorophenyl)-2-(methylthio)[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrilefrom Step A was converted to the title compound as a yellow solid. LC-MS355 (M+1).

Example 3

6-(Aminomethyl)-5-(2,4-dichlorophenyl)-2-(methylsulfonyl)[1,2,4]-triazolo[1,5-a]pyrimidin-7-amine,Trifluoroacetic Acid Salt Step A7-Amino-5-(2,4-dichlorophenyl)-2-(methylsulfonyl)[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile

A mixture of 36 mg (0.103 mmol) of7-amino-5-(2,4-dichlorophenyl)-2-(methylthio)[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrilefrom Example 2, Step A, 56 mg (0.25 mmol based on 77% purity) of3-chloroperoxybenzoic acid, and 2 mL of dichloromethane was stirred atambient temperature for 6.5 h. The solution was concentrated, and theresidue was purified by preparative thin-layer chromatography on silicagel (developed in 95:5 dichloromethane:methanol) to give the titlecompound as a yellow solid. LC-MS 383 (M+1).

Step B6-(Aminomethyl)-5-(2,4-dichlorophenyl)-2-(methylsulfonyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amineTrifluoroacetic Acid Salt

The title compound was obtained by reduction of7-amino-5-(2,4-dichlorophenyl)-2-(methylsulfonyl)[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrilefrom Step A, essentially by the procedure of Example 1, Step B, exceptthat the borane reduction was conducted under sonication in anultrasound bath at ambient temperature. LC-MS 387 (M+1).

Example 4

6-(Aminomethyl)-5-(2,4-dichlorophenyl)-2-piperazin-2-yl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,Trifluoroacetic Acid Salt Step A7-Amino-5-(2,4-dichlorophenyl)-2-pyrazin-2-yl[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile

In analogy to the procedure of Example 1, Step A (but using gradientelution with 5-10% methanol in dichloromethane for purification),5-pyrazin-2-yl-1H-1,2,4-triazol-3-amine (Intermediate 15) and(2,4-dichlorobenzylidene)malononitrile (Intermediate 1) were reacted togive the title compound as a dark reddish-orange solid. LC-MS 383 (M+1).

Step B6-(Aminomethyl)-5-(2,4-dichlorophenyl)-2-piperazin-2-yl[1,2,4]triazolo[1,5-a]pyrimidin-7-amineTrifluoroacetic Acid Salt

Borane reduction of7-amino-5-(2,4-dichlorophenyl)-2-pyrazin-2-yl[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrilefrom Step A according to the method of Example 3, Step B, afforded thetitle compound as a pale yellow solid. LC-MS 393 (M+1).

Example 5

3-(Aminomethyl)-2-(2,4-dichlorophenyl)-7,8,9,10-tetrahydropyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidin-4-amine,Trifluoroacetic Acid Salt Step A4-amino-2-(2,4-dichlorophenyl)pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Commercial 1H-pyrazolo[3,4-b]pyridin-3-amine and(2,4-dichlorobenzylidene)malononitrile (Intermediate 1) were reactedaccording to the procedure of Example 1, Step A, and the crude productwas purified by preparative HPLC (C18 reverse phase column, gradientelution with 10-80% acetonitrile in water containing 0.05%trifluoroacetic acid) to give the title compound as a yellow solid.LC-MS 355 (M+1).

Step B3-(Aminomethyl)-2-(2,4-dichlorophenyl)-7,8,9,10-tetrahydropyrido-[2′,3′:3,4]pyrazolo[1,5-a]pyrimidin-4-amine,Trifluoroacetic Acid Salt

Borane reduction of4-amino-2-(2,4-dichlorophenyl)pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine-3-carbonitrilefrom Step A according to the method of Example 3, Step B, afforded thetitle compound. LC-MS 363 (M+1).

Example 6

Ethyl7-amino-6-(aminomethyl)-5-(2,4-dichlorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate,Trifluoroacetic Acid Salt Step A Ethyl7-amino-6-cyano-5-(2,4-dichlorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

Commercial 3-amino-4-carbethoxypyrazole and(2,4-dichlorobenzylidene)malononitrile (Intermediate 1) were reactedaccording to the procedure of Example 1, Step A, and the crude productwas purified by preparative HPLC(C18 reverse phase column, gradientelution with 30-80% acetonitrile in water containing 0.05%trifluoroacetic acid) to give the title compound as a reddish-orangesolid. LC-MS 376 (M+1).

Step B Ethyl7-amino-6-(aminomethyl)-5-(2,4-dichlorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate,Trifluoroacetic Acid Salt

Borane reduction of ethyl7-amino-6-cyano-5-(2,4-dichlorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylatefrom Step A according to the procedure of Example 1, Step B, yielded[after separation from a by-product (see Example 7)] the title compoundas a pale yellow solid. LC-MS 380 (M+1).

Example 7

[7-Amino-6-(aminomethyl)-5-(2,4-dichlorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanolTrifluoroacetic Acid Salt

Borane reduction of ethyl7-amino-6-cyano-5-(2,4-dichlorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylatefrom Example 6, Step A, according to the procedure of Example 1, Step B,yielded [after separation from a by-product (see Example 6)] the titlecompound as a pale yellow solid. LC-MS 338 (M+1).

Example 8

Ethyl7-amino-6-(aminomethyl)-5-mesitylpyrazolo[1,5-a]pyrimidine-3-carboxylate,Trifluoroacetic Acid Salt Step A Ethyl7-amino-6-cyano-5-mesitylpyrazolo[1,5-a]pyrimidine-3-carboxylate

A solution of 155 mg (1 mmol) of 3-amino-4-carbethoxypyrazole and 196 mg(1 mmol) of (mesitylmethylene)malononitrile (Intermediate 3) in 3 mL ofanhydrous pyridine was stirred at reflux under air for 3 days and thencooled and concentrated in vacuo. Because LC-MS indicated the presenceof considerable dihydro intermediate, 112 mg (0.49 mmol) of2,3-dichloro-5,6-cyano-1,4-benzoquinone (DDQ) and 3 mL of isopropanolwere added to the residue, and the mixture was stirred at ambienttemperature for 1 h. The mixture was concentrated in vacuo, and theresidue was purified by flash chromatography on silica gel (elution with2% methanol in dichloromethane) to give the title compound as an orangesolid. LC-MS 350 (M+1).

Step B Ethyl7-amino-6-(aminomethyl)-5-mesitylpyrazolo[1,5-a]pyrimidine-3-carboxylate,Trifluoroacetic Acid Salt

Borane reduction of ethyl7-amino-6-cyano-5-mesitylpyrazolo[1,5-a]pyrimidine-3-carboxylate fromStep A according to the procedure of Example 1, Step B, yielded (afterseparation from a by-product corresponding to Example 9) the titlecompound as a brownish solid. LC-MS 354 (M+1).

Example 9

6-(Aminomethyl)-5-mesityl-3-methylpyrazolo[1,5-a]pyrimidin-7-amine,Trifluoroacetic Acid Salt Step A Ethyl7-amino-6-cyano-5-mesitylpyrazolo[1,5-a]pyrimidine-3-carboxylate

In a variation of Example 8, Step A, a solution of 5.69 g (36.7 mmol) of3-amino-4-carbethoxypyrazole and 6.00 g (30.6 mmol) of(mesitylmethylene)malononitrile (Intermediate 3) in 34 mL of anhydrouspyridine was stirred at reflux under air for 6 days. The dark solutionwas cooled and concentrated in vacuo. The residue was flashchromatographed on silica gel (gradient elution with 20-50% ethylacetate in hexane) to give the crude product as a dark solidcontaminated with another regioisomer. This material was dissolved indiethyl ether containing a little ethyl acetate. Addition of hexaneprecipitated a dark, tacky solid. This semisolid was collected andredissolved in 9:1 dichloromethane:methanol. Addition of hexane resultedin precipitation. The precipitate was collected on a filter and dried togive the title compound as a yellow solid. LC-MS 350 (M+1).

Step B6-(Aminomethyl)-5-mesityl-3-methylpyrazolo[1,5-a]pyrimidin-7-amine,Trifluoroacetic Acid Salt

A solution of 1.05 g (3 mmol) of ethyl7-amino-6-cyano-5-mesitylpyrazolo[1,5-a]pyrimidine-3-carboxylate fromStep A in 12 mL of anhydrous tetrahydrofuran was stirred under nitrogenat ambient temperature as 12 mL (12 mmol) of 1M borane-tetrahydrofurancomplex in tetrahydrofuran was added gradually by syringe. The mixturewas stirred overnight with sonication in an ultrasound bath. Next, themixture was quenched by cautious gradual addition of approximately 3.6mL (43 mmol) of concentrated hydrochloric acid (gas evolution) followedby addition of about 50 mL of methanol. The resulting solution wasstirred at reflux for 2 h and then evaporated to dryness. Purificationof the residual foam by preparative HPLC(C18 reverse phase column,gradient elution with 5-37% acetonitrile in water containing 0.05%trifluoroacetic acid) yielded the title compound as a white solid. LC-MS296 (M+1).

Example 10

3-(Aminomethyl)-2-mesityl-7H,9H-thieno[3′,4′:3,4]pyrazolo[1,5-a]pyrimidin-4-amineStep A4-Amino-2-mesityl-7H,9H-thieno[3′,4′:3,4]pyrazolo[1,5-a]pyrimidine-3-carbonitrile

A solution of 284 mg (2.01 mmol) of4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-amine (Intermediate 21) and 395 mg(2.01 mmol) of (mesitylmethylene)malononitrile (Intermediate 3) in 5 mLof anhydrous pyridine was stirred at reflux under air overnight(protected from moisture with a calcium sulfate drying tube) and thencooled and concentrated in vacuo. The residue was stirred with 20 mL ofmethanol and filtered to remove some insoluble material, which waswashed with an additional 5 mL of methanol. The combined filtrate andwashings were concentrated. Purification of the residue by flashchromatography on silica gel (gradient elution with 5-15% ethyl acetatein hexane) afforded the title compound as a solid. LC-MS 336 (M+1).

Step B3-(Aminomethyl)-2-mesityl-7H,9H-thieno[3′,4′:3,4]pyrazolo[1,5-a]pyrimidin-4-amine

A suspension of 81 mg (0.24 mmol) of4-amino-2-mesityl-7H,9H-thieno[3′,4′:3,4]pyrazolo[1,5-a]pyrimidine-3-carbonitrilefrom Step A in 1.2 mL of anhydrous tetrahydrofuran was stirred undernitrogen in an ultrasound bath as 1.2 mL (1.2 mmol) of 1Mborane-tetrahydrofuran complex in tetrahydrofuran was added gradually bysyringe. The mixture was stirred overnight with intermittent sonication.Next, the mixture was quenched by cautious gradual addition of 0.36 mL(4.32 mmol) of concentrated hydrochloric acid (gas evolution) followedby addition of 1.2 mL of methanol. The resulting solution was stirred ina sealed tube with heating in an oil bath at 80° C. for 4 h. Thesolution was evaporated to dryness and re-concentrated twice frommethanol. The residue was converted to free base form by passage througha pre-washed SCX ion exchange cartridge. After flushing the column withmethanol to remove trifluoroacetic acid, elution with 1M ammonia inmethanol afforded the crude product. Further purification by flashchromatography on silica gel (elution with 98:2:0.4dichloromethane:methanol:concentrated ammonium hydroxide) yielded thetitle compound. LC-MS 340 (M+1).

Essentially following the procedures outlined for Examples 1-10, thecompounds listed in Tables 2 and 3 were prepared from the intermediatesdescribed herein.

TABLE 2

Mass Spectrum Example R¹ Z (M + 1) 11 H 2,4-Cl₂—Ph 309 12 Me 2,4-Cl₂—Ph323 13 CF₃ 2,4-Cl₂—Ph 377 14 HOCH₂ 2,4-Cl₂—Ph 339 15 cyclopropyl2,4-Cl₂—Ph 349 16 cyclobutyl 2,4-Cl₂—Ph 363 17 HO 2,4-Cl₂—Ph 325 18 H₂N2,4-Cl₂—Ph 324 19 morpholin-4-yl 2,4-Cl₂—Ph 394 20 H 2-F-4-Cl—Ph 293 21CF₃ 2-F-4-Cl—Ph 361 22 H₂N 2-F-4-Cl—Ph 308 23 H 2-Me-4-Cl—Ph 289 24 CF₃2-Me-4-Cl—Ph 357 25 HOCH₂ 2-Me-4-Cl—Ph 319 26 H₂N 2-Me-4-Cl—Ph 304 27 H2,4-Me₂—Ph 269 28 CF₃ 2,4-Me₂—Ph 337 29 HOCH₂ 2,4-Me₂—Ph 299 30cyclopropyl 2,4-Me₂—Ph 309 31 cyclobutyl 2,4-Me₂—Ph 323 32 H₂N2,4-Me₂—Ph 284 33 MeS 2,4-Me₂—Ph 315 34 MeSO₂ 2,4-Me₂—Ph 347 35 H2-MeO-4-Cl—Ph 305 36 CF₃ 2-MeO-4-Cl—Ph 373 37 HOCH₂ 2-MeO-4-Cl—Ph 335 38cyclobutyl 2-MeO-4-Cl—Ph 359 39 H₂N 2-MeO-4-Cl—Ph 320 40 H 2-F-4-CF₃—Ph327 41 H₂N 5-Cl₂-pyridin-2-yl 325 42 CF₃ 2,3-F₂-4-Me—Ph 359 43 H₂N2,3-F₂-4-Me—Ph 306 44 H₂N 2,4,5-F₃—Ph 310 45 H 2,4,6-Me₃—Ph 283 46 CF₃2,4,6-Me₃—Ph 351 47 HOCH₂ 2,4,6-Me₃—Ph 313 48 cyclopropyl 2,4,6-Me₃—Ph323 49 H₂N 2,4,6-Me₃—Ph 298 50 Me₂N 2,4,6-Me₃—Ph 326 51 MeS 2,4,6-Me₃—Ph329 52 Me₂N 2,4,6-Me₃—Ph 326 53 H 2,4,6-Cl₃—Ph 343 54 H₂N 2,4,6-Cl₃—Ph358 55 H 2,4-Cl₂-6-MeO 339 56 CF₃ 2,4-Cl₂-6-MeO 407 57 HOCH₂2,4-Cl₂-6-MeO 369 58 cyclopropyl 2,4-Cl₂-6-MeO 379 59 H₂N 2,4-Cl₂-6-MeO354

TABLE 3

Mass Spectrum Example R¹ R² Z (M + 1) 60 Me H 2,4-Cl₂—Ph 322 61 H Ph2,4-Cl₂—Ph 384 62 H 2-pyridyl 2,4-Cl₂—Ph 385 63 H 3-pyridyl 2,4-Cl₂—Ph385 64 H 4-pyridyl 2,4-Cl₂—Ph 385 65 H —Me-thiazol-2-yl 2,4-Cl₂—Ph 40566 H MeSO₂ 2,4-Cl₂—Ph 386 67 H Me 2-F-4-Cl—Ph 306 68 H HOCH₂ 2-F-4-Cl—Ph322 69 H —Me-thiazol-2-yl 2-F-4-Cl—Ph 389 70 Me H 2-Me-4-Cl—Ph 302 71 HMe 2-Me-4-Cl—Ph 302 72 H EtO₂C 2-Me-4-Cl—Ph 360 73 H Me 2,4-Me₂—Ph 28274 H EtO₂C 2,4-Me₂—Ph 340 75 Me H 2-MeO-4-Cl—Ph 318 76 H Me2-MeO-4-Cl—Ph 318 77 H H 2,4,6-Me₃—Ph 282 78 Me Me 2,4,6-Me₃—Ph 310 79 H2-pyridyl 2,4,6-Me₃—Ph 359 80 H 4-pyridyl 2,4,6-Me₃—Ph 359 81 H5-Me₂N-1,3,4- 2,4,6-Me₃—Ph 393 oxadiazol-2-yl 82 H H 2,4,6-Cl₃—Ph 342 83Me H 2,4,6-Cl₃—Ph 356 84 H Me 2,4,6-Cl₃—Ph 356 85 H EtO₂C 2,4,6-Cl₃—Ph414 86 H MeSO₂ 2,4,6-Cl₃—Ph 420 87 Me Cl 2,4,6-Me₃—Ph 330 88 H H₂NCH₂2,4,6-Me₃—Ph 294 [(M-NH3)+1] 89 H Me 2,4-Cl₂-6-MeO 352 90 H MeO2,4,6-Me₃—Ph 312

EXAMPLE OF A PHARMACEUTICAL FORMULATION

As a specific embodiment of an oral pharmaceutical composition, a 100 mgpotency tablet is composed of 100 mg of any of Examples 1-10, 268 mgmicrocrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg ofmagnesium stearate. The active, microcrystalline cellulose, andcroscarmellose are blended first. The mixture is then lubricated bymagnesium stearate and pressed into tablets.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inresponsiveness of the mammal being treated for any of the indicationswith the compounds of the invention indicated above. The specificpharmacological responses observed may vary according to and dependingupon the particular active compounds selected or whether there arepresent pharmaceutical carriers, as well as the type of formulation andmode of administration employed, and such expected variations ordifferences in the results are contemplated in accordance with theobjects and practices of the present invention. It is intended,therefore, that the invention be defined by the scope of the claimswhich follow and that such claims be interpreted as broadly as isreasonable.

1. A compound of the formula I:

or a pharmaceutically acceptable salt thereof; wherein each n isindependently 0, 1, 2, or 3; A is CR²; W¹ and W² are independently H orC₁₋₄ alkyl; or W¹ and W² together with the carbon atom to which they areattached form a 3- to 6-membered carbocyclic ring; Z is phenyl orpyridyl, each of which is substituted with one to five R³ substitutents;R¹ and R² are each independently selected from the group consisting of:(1) hydrogen, (2) C₁₋₁₀ alkyl, wherein alkyl is unsubstituted orsubstituted with one to five substituents independently selected from:(a) halogen, (b) hydroxy, (c) OR⁴, (d) SR⁴, (e) S(O)₁₋₂R⁴, (f) SO₂NR⁵R⁶,(g) NR⁵R⁶, (h) NHSO₂R⁴, (i) N(C₁₋₆ alkyl)SO₂R⁴, (j) NHCONR⁵R⁶, (k)N(C₁₋₆ alkyl)CONR⁵R⁶, (l) NHCO₂R⁴, (m) N(C₁₋₆ alkyl)CO₂R⁴, (n) OCONR⁵R⁶,(o) CN, (p) CO₂H, (q) CO₂C₁₋₆ alkyl, (r) CONR⁵R⁶, and (s) phenyl, whichis unsubstituted or substituted with one to five substituentsindependently selected from halogen, CN, OH, R⁴, OR⁴, NHSO₂R⁴, N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CO₂H, and CO₂C₁₋₆ alkyl,(3) phenyl, wherein phenyl is unsubstituted or substituted with one tofive substituents independently selected from halogen, R⁴, OH, OR⁴,NHSO₂R⁴, N(C₁₋₆ alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CN, CO₂H,and CO₂C₁₋₆ alkyl, (4) (CH₂)_(n)-heteroaryl, wherein heteroaryl isunsubstituted or substituted with one to three substituentsindependently selected from halogen, OH, R⁴, OR⁴, NHSO₂R⁴,N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CN, CO₂H, andCO₂C₁₋₆ alkyl, (5) (CH₂)_(n)-heterocyclyl, wherein heterocyclyl isunsubstituted or substituted with one to three substituentsindependently selected from oxo, halogen, OH, R⁴, OR⁴, NHSO₂R⁴,N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CN, CO₂H, andCO₂C₁₋₆ alkyl, (6) (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl isunsubstituted or substituted with one to five substituents independentlyselected from halogen, OH, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyland alkoxy are unsubstituted or substituted with one to five halogens,(7) hydroxy, (8) OR⁴, (9) SR⁴, (10) S(O)₁₋₂R⁴, (11) SO₂NR⁵R⁶, (12)NR⁵R⁶, (13) NHSO₂R⁴, (14) N(C₁₋₆ alkyl)SO₂R⁴, (15) NHCONR⁵R⁶, (16)N(C₁₋₆ alkyl)CONR⁵R⁶, (17) NHCO₂R⁴, (18) N(C₁₋₆ alkyl)CO₂R⁴, (19)OCONR⁵R⁶, (20) CN, (21) CO₂H, (22) CO₂C₁₋₆ alkyl, (23) CONR⁵R⁶, and (24)halogen; each R³ is independently selected from the group consisting of:(1) halogen, (2) C₁₋₆ alkyl, unsubstituted or substituted with one tofive substituents independently selected from halogen, hydroxy, and C₁₋₄alkoxy, (3) C₁₋₆ alkoxy, unsubstituted or substituted with one to fivesubstituents independently selected from halogen, hydroxy, and C₁₋₄alkoxy, (4) hydroxy, (5) O(CH₂)_(n)-aryl, wherein aryl is unsubstitutedor substituted with one to five substituents independently selected fromhalogen, methyl, hydroxy, and methoxy, and (6) O(CH₂)_(n)-heteroaryl,wherein heteroaryl is unsubstituted or substituted with one to fivesubstituents independently selected from halogen, methyl, hydroxy, andmethoxy; R⁴ is C₁₋₆ alkyl, unsubstituted or substituted with one to fivesubstituents independently selected from halogen, hydroxy, methoxy,CO₂H, and CO₂C₁₋₆ alkyl; and R⁵ and R⁶ are each independently selectedfrom the group consisting of: (1) hydrogen, (2) C₁₋₆ alkyl,unsubstituted or substituted with one to five substituents independentlyselected from halogen, hydroxy, and C₁₋₆ alkoxy, (3) (CH₂)_(n)—C₃₋₆cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with oneto five substituents independently selected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens, and (4) (CH₂)_(n)-phenyl, whereinphenyl is unsubstituted or substituted with substituents independentlyselected from halogen, OH, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyland alkoxy are unsubstituted or substituted with one to five halogens;or wherein R⁵ and R⁶ together with the nitrogen atom to which they areattached form a heterocyclic ring selected from azetidine, pyrrolidine,piperidine, piperazine, and morpholine wherein said heterocyclic ring isunsubstituted or substituted with one to five substituents independentlyselected from halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, whereinalkyl and alkoxy are unsubstituted or substituted with one to fivehalogens.
 2. The compound of claim 1 wherein W¹ and W² are H.
 3. Thecompound of claim 2 wherein Z is phenyl phenyl which is substituted withtwo to five R³ substituents; each n is independently 0, 1, 2, or 3; R¹is selected from the group consisting of: (1) hydrogen, (2) C₁₋₄ alkyl,wherein alkyl is unsubstituted or substituted with one to fivesubstituents independently selected from: (a) halogen, (b) hydroxy, (c)OR⁴, (d) SR⁴, and (e) NR⁵R⁶, (3) (CH₂)_(n)—C₃₋₆ cycloalkyl, whereincycloalkyl is unsubstituted or substituted with one to five substituentsindependently selected from halogen, OH, C₁₋₆ alkyl, and C₁₋₆ alkoxy,(4) hydroxy, (5) OR⁴, (6) SR⁴, and (7) NR⁵R⁶; R² is selected from thegroup consisting of: (1) hydrogen, (2) C₁₋₁₀ alkyl, wherein alkyl isunsubstituted or substituted with one to five substituents independentlyselected from: (a) halogen, (b) hydroxy, (c) OR⁴, (d) SR⁴, (e)S(O)₁₋₂R⁴, (f) SO₂NR⁵R⁶, (g) NR⁵R⁶, (h) NHSO₂R⁴, (i) N(C₁₋₆alkyl)SO₂R⁴,(j) NHCONR⁵R⁶, (k) N(C₁₋₆ alkyl)CONR⁵R⁶, (l) NHCO₂R⁴, (m) N(C₁₋₆alkyl)CO₂R⁴, (n) OCONR⁵R⁶, (o) CN, (p) CO₂H, (q) CO₂C₁₋₆ alkyl, (r)CONR⁵R⁶, and (s) phenyl, which is unsubstituted or substituted with oneto five substituents independently selected from halogen, CN, OH, R⁴,OR⁴, NHSO₂R⁴, N(C₁₋₆ alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CO₂H,and CO₂C₁₋₆ alkyl, (3) phenyl which is unsubstituted or substituted withone to five substituents independently selected from halogen, R⁴, OH,OR⁴, NHSO₂R⁴, N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CN,CO₂H, and CO₂C₁₋₆ alkyl, (4) (CH₂)_(n)-heteroaryl, wherein heteroaryl isunsubstituted or substituted with one to three substituentsindependently selected from halogen, OH, R⁴, OR⁴, NHSO₂R⁴,N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CN, CO₂H, andCO₂C₁₋₆ alkyl, (5) (CH₂)_(n)-heterocyclyl, wherein heterocyclyl isunsubstituted or substituted with one to three substituentsindependently selected from oxo, halogen, OH, R⁴, OR⁴, NHSO₂R⁴,N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CN, CO₂H, andCO₂C₁₋₆ alkyl, (6) (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl isunsubstituted or substituted with one to five substituents independentlyselected from halogen, OH, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyland alkoxy are unsubstituted or substituted with one to five halogens,(7) hydroxy, (8) OR⁴, (9) SR⁴, (10) S(O)₁₋₂R⁴, (11) SO₂NR⁵R⁶, (12)NR⁵R⁶, (13) NHSO₂R⁴, (14) N(C₁₋₆alkyl)SO₂R⁴, (15) NHCONR⁵R⁶, (16) N(C₁₋₆alkyl)CONR⁵R⁶, (17) NHCO₂R⁴, (18) N(C₁₋₆ alkyl)CO₂R⁴, (19) OCONR⁵R⁶,(20) CN, (21) CO₂H, (22) CO₂C₁₋₆ alkyl, (23) CONR⁵R⁶, and (24) halogen;each R³ is independently selected from the group consisting of: (1)halogen, (2) C₁₋₄ alkyl, unsubstituted or substituted with one to fivesubstituents independently selected from halogen, hydroxy, and C₁₋₄alkoxy, (3) C₁₋₄ alkoxy, unsubstituted or substituted with one to fivesubstituents independently selected from halogen, hydroxy, and C₁₋₄alkoxy, (4) hydroxy, (5) O(CH₂)_(n)-aryl, wherein aryl is unsubstitutedor substituted with one to five substituents independently selected fromhalogen, methyl, hydroxy, and methoxy, and (6) O(CH₂)_(n)-heteroaryl,wherein heteroaryl is unsubstituted or substituted with one to fivesubstituents independently selected from halogen, methyl, hydroxy, andmethoxy; R⁴ is C₁₋₆ alkyl, unsubstituted or substituted with one to fivesubstituents independently selected from halogen, hydroxy, and methoxy;and R⁵ and R⁶ are independently selected from the group consisting of:(1) hydrogen, (2) C₁₋₄ alkyl, unsubstituted or substituted with one tofive substituents independently selected from halogen, hydroxy, and C₁₋₄alkoxy, and (3) (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl isunsubstituted or substituted with one to five substituents independentlyselected from halogen, OH, C₁₋₄ alkyl, and C₁₋₄ alkoxy, wherein alkyland alkoxy are unsubstituted or substituted with one to five halogens;or wherein R⁵ and R⁶ together with the nitrogen atom to which they areattached form a heterocyclic ring selected from azetidine, pyrrolidine,piperidine, piperazine, and morpholine.
 4. The compound of claim 1 ofthe structural formula Ic:

wherein each n is independently 0, 1, 2, or 3; A is CR²; R³ is chloro ormethyl, which is unsubstituted or substituted with one to three fluorineatoms; R⁷ is selected from the group consisting of: (1) hydrogen, (2)halogen, (3) C₁₋₆ alkyl, unsubstituted or substituted with one to fivesubstituents independently selected from halogen, hydroxy, and C₁₋₄alkoxy, (4) C₁₋₆ alkoxy, unsubstituted or substituted with one to fivesubstituents independently selected from halogen, hydroxy, and C₁₋₄alkoxy, (5) hydroxy, (6) O(CH₂)_(n)-aryl, wherein aryl is unsubstitutedor substituted with one to five substituents independently selected fromhalogen, methyl, hydroxyl, and methoxy, and (7) O(CH₂)_(n)-heteroaryl,wherein heteroaryl is unsubstituted or substituted with one to fivesubstituents independently selected from halogen, methyl, hydroxyl, andmethoxy; R¹ is selected from the group consisting of: (1) hydrogen, (2)C₁₋₄ alkyl, wherein alkyl is unsubstituted or substituted with one tofive substituents independently selected from: (a) halogen, (b) hydroxy,(c) OR⁴, (d) SR⁴, and (e) NR⁵R⁶, (3) (CH₂)_(n)—C₃₋₆ cycloalkyl, whereincycloalkyl is unsubstituted or substituted with one to five substituentsindependently selected from halogen, OH, C₁₋₆ alkyl, and C₁₋₆ alkoxy,(4) hydroxy, (5) OR⁴, (6) SR⁴, and (7) NR⁵R⁶; and R² is selected fromthe group consisting of: (1) hydrogen, (2) C₁₋₁₀ alkyl, wherein alkyl isunsubstituted or substituted with one to five substituents independentlyselected from: (a) halogen, (b) hydroxy, (c) OR⁴, (d) SR⁴, (e)S(O)₁₋₂R⁴, (f) SO₂NR⁵R⁶, (g) NR⁵R⁶, (h) NHSO₂R⁴, (i) N(C₁₋₆alkyl)SO₂R⁴,(j) NHCONR⁵R⁶, (k) N(C₁₋₆ alkyl)CONR⁵R⁶, (l) NHCO₂R⁴, (m) N(C₁₋₆alkyl)CO₂R⁴, (n) OCONR⁵R⁶, (o) CN, (p) CO₂H, (q) CO₂C₁₋₆ alkyl, (r)CONR⁵R⁶, and (s) phenyl, which is unsubstituted or substituted with oneto five substituents independently selected from halogen, CN, OH, R⁴,OR⁴, NHSO₂R⁴, N(C₁₋₆ alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CO₂H,and CO₂C₁₋₆ alkyl, (3) phenyl which is unsubstituted or substituted withone to five substituents independently selected from halogen, R⁴, OH,OR⁴, NHSO₂R⁴, N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CN,CO₂H, and CO₂C₁₋₆ alkyl, (4) (CH₂)_(n)-heteroaryl, wherein heteroaryl isunsubstituted or substituted with one to three substituentsindependently selected from halogen, OH, R⁴, OR⁴, NHSO₂R⁴,N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CN, CO₂H, andCO₂C₁₋₆ alkyl, (5) (CH₂)_(n)-heterocyclyl, wherein heterocyclyl isunsubstituted or substituted with one to three substituentsindependently selected from oxo, halogen, OH, R⁴, OR⁴, NHSO₂R⁴,N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁵R⁶, NR⁵R⁶, CONR⁵R⁶, CN, CO₂H, andCO₂C₁₋₆ alkyl, (6) (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl isunsubstituted or substituted with one to five substituents independentlyselected from halogen, OH, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyland alkoxy are unsubstituted or substituted with one to five halogens,(7) hydroxy, (8) OR⁴, (9) SR⁴, (10) S(O)₁₋₂R⁴, (11) SO₂NR⁵R⁶, (12)NR⁵R⁶, (13) NHSO₂R⁴, (14) N(C₁₋₆alkyl)SO₂R⁴, (15) NHCONR⁵R⁶, (16) N(C₁₋₆alkyl)CONR⁵R⁶, (17) NHCO₂R⁴, (18) N(C₁₋₆ alkyl)CO₂R⁴, (19) OCONR⁵R⁶,(20) CN, (21) CO₂H, (22) CO₂C₁₋₆ alkyl, (23) CONR⁵R⁶, and (24) halogen.5. The compound of claim 1 which is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition which comprises a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 7. The pharmaceutical composition of claim 6additionally comprising metformin.
 8. A method for treating non-insulindependent (Type 2) diabetes in a mammal in need thereof which comprisesthe administration to the mammal of a therapeutically effective amountof a compound of claim 1.